AJP - Heart Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 290: H1729-H1739, 2006; doi:10.1152/ajpheart.01103.2005
0363-6135/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (15)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, J.
Right arrow Articles by Goligorsky, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, J.
Right arrow Articles by Goligorsky, M. S.

INVITED REVIEW

Premature senescence of endothelial cells: Methusaleh's dilemma

Jun Chen and Michael S. Goligorsky

Departments of Medicine and Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York


   ABSTRACT
TOP
 ABSTRACT
HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
Senescence has been considered a programmed cellular response, parallel to apoptosis, that is turned on when a cell reaches Hayflick's limit. Once cells enter the senescence program, they cease to proliferate and undergo a series of morphological and functional changes. Studies support a central role for Rb protein in controlling this process after it receives senescent signals from the p53 and p16 pathways. Cellular senescence is considered an essential contributor to the aging process and has been shown to be an important tumor suppression mechanism. In addition, emerging evidence suggests that senescence may also be involved in the pathogenesis of stem cell dysfunction and chronic human diseases. Under these circumstances cells undergo stress-induced premature senecence, which has several specific features. Focusing on endothelial cells, we discuss recent advances in our understanding of the stresses and their pathways that prompt the premature senescence response, evaluate their correlation with the apoptotic response, and examine their links to the development of chronic diseases and the impaired function of endothelial progenitor cells, with the emphasis on vasculopathy. Emerging novel therapeutic interventions based on recent experimental findings are also reviewed.

stress-induced premature senescence; endothelial progenitor cell; vasculopathy; metabolic syndrome; nephropathy


   HISTORY OF SENESCENCE RESEARCH
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
Cessation of cell division after extended propagation in culture was first observed by Hayflick and Moorhead (61) in normal human fibroblasts in 1961, igniting research on cell senescence. This type of senescence, which usually requires weeks or months of culture, appeared to be related to the limited number of divisions that any particular cell type could undergo (thus determining its lifespan) and is termed replicative senescence. The bulk of evidence has linked senescence to the attrition of telomeres (60), which leads to chromosomal instability. In addition to telomere attrition, some stressors elicit a similar growth arrest within just a few days, referred to as stress-induced premature senescence (SIPS). The stressors that have been identified include activated oncogenes (17, 46, 117), DNA damage (50, 82, 96), oxidative stress (31, 119), suboptimal cell culture conditions (7, 8), and others (115, 143, 149). In either type of senescence, cells flatten and enlarge, acquiring a "fried egg" appearance. Initially thought to be a cell culture phenomenon, cell senescence has been more recently observed in vivo (30, 41, 44, 147). In addition to the above morphological changes, the recognized biomarkers of senescent cells include staining for beta-galactosidase at pH of 6.0 [known as senescence-associated beta-galactosidase (SA-beta-gal) as opposed to the endogenous lysosomal enzyme detected at pH of 4.0 in normal cells]; decreased replicative capacity; increased expression of p53, p21, and/or p16 (vide infra) or other cyclin-dependent kinase inhibitors (e.g. p27 and p15); and accumulation of transcriptionally inactive heterochromatic structure [senescence-associated heterochromatic foci (SAHF)] (113). It is worth noting that many of the concepts related to senescence are developed from studies of human fibroblasts and from some immortalized cell lines; therefore, those concepts may be not fully relevant to primary endothelial cells.


   REGULATION OF SENESCENCE
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
The above changes in cells undergoing replicative or SIPS have been mechanistically linked to the stabilization of p53 and hypophosphorylation of pRb. There is evidence supporting a linear p53-p21-pRb pathway (17, 32, 93) (Fig. 1). Overexpression of the tumor suppressor p53 results in transcriptional activation of many proteins, including p21, an inhibitor of the cyclin E/Cdk2 complex (87). Inhibition of this complex enables the maintenance of the hypophosphorylated (active) state of the Rb protein, which has been shown to interact with the transcription factor E2F family members and silence their transcriptional targets by invoking SAHF formation through the recruitment of heterochromatin proteins to E2F-responsive promoters (113). On the other hand, the activation of p16, an inhibitor of the cyclin D/Cdk4 and D/Cdk6 complex, provides an additional stimulatory pathway that maintains the Rb in its active state and hence leads to the induction of senescence (12, 84). Studies in mouse embryo fibroblasts have provided evidence that two other members of the Rb family, p107 and p130, may also be important factors for the senescent program because their inactivation was found to be necessary and sufficient to prevent senescence in Rb-mutated cells (39, 128). The contribution of these two proteins to the senescent programs in other cell types is currently under investigation.


Figure 1
View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1. Pathways inducing cell senescence and apoptosis. A number of regulatory proteins transmit various stress signals and mediate cell entry into senescence through two cell cycle check-point pathways, p53/p21 and p16. Upregulation of p21 and p16 tumor suppressor can keep Rb in hypophosphorylated growth inhibition form, which prevents the binding of E2F to its targeted gene promoters. Studies have suggested that the DNA damage, initiated by unprotected telomere structure or other stressors, induce cell senescence mainly by activating the ATM-p53-p21-pRb pathway. The p16-pRb pathway may be activated through engagement of p38/MAPK cascade that is initiated by various stressors. Elevated ARF tumor suppressor gene products, p19ARF in mouse or p14ARF in human, can also input the stress signal to p53/p21 pathway via its ability to bind and sequester MDM2 protein and inhibit the MDM-dependent degradation of p53. The activation of p53 pathway may also initiate an apoptotic response. The balanced regulation of these two responses for apoptosis and senescence is currently under investigation.

 
Telomere shortening has been considered a hallmark of replicative senescence. It appears that the unprotected telomere structure can initiate DNA damage response and induce cell senescence by activating the ATM-p53-p21-pRb pathway (64), and that p16 has an important, but nonessential, role in this senescence process in the human fibroblast (20, 78). However, it may still possess a significant role in cells such as human prostate epithelial cells (79). Recent evidence suggests that telomere shortening may be not an indispensable element for SIPS, which can usually be induced in days, and is unaltered by experimental telomere extension through exogenous over expression of human telomerase (hTERT) (53, 110). Oxidative stress and the oncogenic ras expression appear to activate the senescence program mainly by involving the p16-pRb pathway through the mediation of the p38-MAPK signaling cascade (21, 40, 89, 152). Although these processes have been studied separately in vitro to permit dissection of the pathways involved, this does not preclude the possibility that both the telomere shortening-initiated and stress-induced senescent types may jointly contribute to the pathogenic process of chronic diseases in vivo.

It is worth noting that the signal cascades before the activation of p53 and p16 pathways remain poorly understood, and the signal pathway downstream of Rb/E2F that results in the various morphological and functional changes of senescence remains largely unexplored. There is also an ongoing debate as to the necessity and sufficiency of each of these tumor suppressor pathways in cell entry to senescence. In mouse embryo fibroblasts, these pathways may function independently, whereas both pathways may be involved in human fibroblasts (42, 76). It has been proposed that "distinct senescence programs can progress in parallel, resulting in mosaic cultures," here some cells overexpress p21 or p16 or both (12).

Little is known about senescence and SIPS of endothelial cells. In aging vasculature, senescence has been found in association with the accumulation of mitochondria peroxynitrite in endothelial cells (147). Proatherogenic and proinflammatory factors like oxidized LDL, TNF-{alpha}, or hydrogen peroxide have been implicated in SIPS and shown to result in the inhibition of phosphoinositol 3-kinase/Akt and suppression of telomerase activity without discernible attrition of telomeres (16). Chronic exposure of human umbilical vein endothelial cells (HUVEC) to the noncytotoxic doses of tert-butyl-hydroperoxide or to an inhibitor of glutathione synthesis buthionine sulfoxamine resulted in the accelerated development of senescence after 30 versus 46 population doublings (88). This was accompanied by faster shortening of telomeres, their increased heterogeneity, and decreased telomerase activity, suggesting a key role for antioxidant cellular defense, specifically glutathione, in the maintenance of telomerase activity and telomere integrity. We found that culturing HUVEC on the surface of nonenzymatically glycated collagen I leads to increased proportion of SA-beta-gal-positive endothelial cells in a much shorter period of time. Whereas changes of telomeres or in telomerase activity were undetectable compared with cells cultured on native collagen, oxidative stress was markedly increased (30).

Senescent endothelial cells are characterized by decreased production of nitric oxide (NO), changes in expression or phosphorylation of endothelial NO synthase (eNOS), decreased synthesis of prostacyclin, increased expression of plasminogen activator inhibitor-1, and enhanced adhesiveness for monocytes (37, 67, 97, 101, 111, 129). When human endothelial cells enter SIPS under the oxidative stress induced by glycated collagen (GC), we have found that despite an aproximately twofold increase in the expression of immunodetectable eNOS, calcium ionophore-stimulated NO release was suppressed (<50% of control), and 3-nitrotyrosine (3NT)-modified proteins, the footprint of peroxynitrite production, accumulated. NO production and escape from senescence could be achieved by use of a NO donor (hydroxy-L-arginine), superoxide dismutase mimetic manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, (MnTBAP), or peroxynitrite scavenger-antioxidant (ebselen), arguing in favor of oxidonitrosative stress as a proximal cause of SIPS in this model.


   RELATION BETWEEN SENESCENCE AND APOPTOSIS
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
Many of the stressors described above can induce apoptosis as well as initiate the senescent program, and both of these responses have been shown to share some common elements in the stress-activated signal pathways. How the cell chooses between these two responses remains obscure. Several studies have attempted to elucidate the mechanism by which a specific outcome results from a certain type of stress. It has been demonstrated that cells in the S-phase commit to apoptosis when subjected to sublethal concentrations of H2O2; in contrast, cells in the G1 and G2/M phases commit to growth arrest (33). In addition, the degree of the stress seems to play an important role. Whereas a low dose of the oxidative stressor H2O2 can induce senescence in the diploid human fibroblast, apoptosis is the predominant outcome when cells are challenged with higher doses (14). This supports the hypothesis that senescence and apoptosis are two parallel outcomes that are activated after cells suffer irreparable damage. These two pathways may intersect at one or more as-yet-undefined point(s). Whereas cells are induced to apoptosis under stress, they will switch to senescence once their apoptosis pathway has been blocked either by exogenous overexpression of the bcl-2 gene (124) or by applying caspase inhibitors (122). On the other hand, it has been shown that aging enhances the sensitivity of endothelial cells toward apoptotic stimuli (67), and in some cases, the apoptosis program may spontaneously occur in senescent human and bovine endothelial cells (30, 144, 151, 161). In contrast to endothelial cells, human fibroblasts enter a stable growth arrest phenotype at the end of their lifespan and are resistant to various apoptotic stimuli (58). Interestingly, instead of undergoing p53-dependent apoptosis under conditions of DNA damage induced by a variety of genotoxic stressors, senescent fibroblasts underwent necrosis instead, which may result from their failure to stabilize p53 (135). These results again exemplify the varied senescent programs seen in different cell types.


   LYSOSOMAL-MITOCHONDRIAL INTERACTION IN SIPS: A HYPOTHESIS
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
Detection of senescent cells is based on the SA-beta-gal assay, the molecular basis of which is still obscure (41). beta-Gal is a lysosomal hydrolase cleaving beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans. Its pH optimum is acidic (4–4.5), thus the appearance of the enzyme in the cytosol, as it occurs in cell senescence, could signify the loss of enzymatic activity. Why does the enzyme shift from the lysosomes to the cytosol? It has recently been demonstrated that p53 destabilizes and permeabilizes lysosomes (159), and this occurs before the effects of p53 induction on the mitochondrial permeability transition responsible for triggering apoptosis. Therefore, a plausible mechanism for the appearance of SA-beta-gal cytoplasmic staining with the build-up of undegraded gangliosides is emerging. The role of p16, another marker of cell senescence, remains obscure. We hypothesize that as long as cellular gangliosides are below a certain threshold, the predominant effect of stress-induced p53 would be cell cycle arrest and senescence-like phenotype. Upon reaching a threshold level, gangliosides exert their effect on the mitochondrion leading, in tandem with the effect of p53, to the permeability transition, escape of cytochrome c, ATP, caspases, and apoptotic protease-activating factor-1, formation of apoptosomal complex (700 kDa), which cleaves downstream caspases, and heralds the cell's commitment to apoptosis (103). Thus, the accumulation of gangliosides, according to our hypothesis, serves as a switch of p53, and/or possibly p16, leading from cell senescence to apoptosis, as schematically depicted in Fig. 2. Though it is admittedly a simplified view of much more complex relations, it is a plausible roadmap toward understanding the pathogenesis of premature cell senescence and its potential link to apoptosis. In support of this scenario, the role of lipids in the maturation of phagolysosomes has recently been discovered (2). In our preliminary experiments, endothelial cells pretreated with an inhibitor of glucosoceramide-based glycosphingolipids synthesis, including ganglioside synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholinopropanol (10–100 nM) or its inactive analog, synthesized in Shayman's laboratory (1, 92), were subjected to oxidative stress, and the proportion of apoptotic and senescent HUVEC was quantified 3 days later. Whereas inhibition of gangliosides synthesis did not appreciably affect cell senescence, it clearly prevented development of apoptosis (data not shown). These findings further support the proposed model where accumulation of gangliosides acts as a switch from senescence to apoptosis.


Figure 2
View larger version (27K):
[in this window]
[in a new window]
  		Fig. 2. Hypothetical involvement of dysfunctional lysosome in premature senescence. It has recently been demonstrated that p53 destabilizes and permeabilizes lysosomes, and this occurs before p53 effects on mitochondrial permeability transition and commitment to apoptosis. Appearance of beta-Gal, a lysosomal hydrolase, in the cytosol, as it occurs in cell senescence, could signify the loss of its enzymatic activity and the subsequent build-up of undegraded gangliosides. We hypothesize that as long as cellular gangliosides are below a certain threshold, the predominant effect of stress-induced p53 would be cell cycle arrest and senescence-like phenotype. Upon reaching a threshold level, gangliosides exert their effect on the mitochondrion leading, in tandem with the effect of p53, to the permeability transition, escape of cytochrome c, ATP, caspases and protease activating factor-1 (APAF-1), formation of apoptosomal complex (700 kDa), which cleaves downstream caspases and heralds cell's commitment to apoptosis. Numbers along the pathways denote the sequence of events.

 

   SENESCENCE AND DISEASES
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
In the field of cancer biology, suppression of senescence invariably predisposes animals to tumorigenesis, giving rise to the belief that cell senescence may have a protective role in vivo (3, 24, 100, 133, 137). Under certain irreparable stresses, normal cells will commit to a senescence program in which the senescent cells retain a relatively intact structure. One can speculate that this may help to maintain tissue structure in the event of sudden and diffuse cell death. However, senescence results in many deleterious structural changes, such as increased adhesion to extracellular matrix while losing cell-cell contacts and dramatic changes in chromatin structure and gene expression (113, 136, 138). In addition, senescence impairs normal cell function (25). In HIV-infected subjects, CD8+ T lymphocytes that displayed short telomeres could no longer proliferate and lost their cytotoxic efficiency to combat the virus (38, 43). Our in vitro studies indicate that prematurely senescent endothelial cells showed evidence of an impaired arginine-eNOS-NO functional system, changes similar to the aged endothelium of macrovasculature (147).

Evidence points to an important contribution of senescence to certain age-related diseases as has been suggested by our recent studies and the studies from other research groups. Accumulation of senescent myocytes with significant telomeric shortening has been detected in aged hearts with dilated cardiomyopathy (34). Cellular senescence also has a proposed role in the deterioration of renal graft function, which has been associated with telomere shortening and subsequent activation of p21 and p16 (81, 104). In human atherosclerotic lesions, overexpression of p53 and p21 has been found in nonproliferating endothelial and smooth muscle cells (71), and SA-beta-gal-positive cells have been detected in human atherosclerotic plaques in the coronary artery and in injured rabbit carotid arteries (45, 107, 108). In Zucker diabetic fatty rats, we observed an increase in the number of SA-beta-gal-positive cells in the aortic endothelium and at ostia of intercostal arteries accompanied by upregulated p53, p21, and p16 expression as well as elevated oxidative stress (18, 30). The development of diabetic microvasculopathy may also be related to the endothelial senescence as discussed in more detail later in this review.

Interestingly, it has been noticed that, even though mitotically inactive, senescent cells are far from being physiologically inert. Many genes in senescent cells display higher expression levels that do not merely correlate with cell cycle arrest (160). Senescent cells can secrete proteins, including degradative enzymes, inflammatory cytokines, and growth factors that may stimulate tissue aging and tumorigenesis and hence possess a more complex role in promoting chronic diseases (25, 26, 156). For instance, an immortal, but nontumorigenic, mouse mammary epithelial cell line will acquire tumorigenic capability and form malignant tumors when injected into mice with irradiation-induced senescent human fibroblasts (118). This was at least partly mediated by matrix metalloproteinase-3, an enzyme secreted by the senescent cells.

Recently, endothelial progenitor cells (EPCs) have been shown to have an important role in maintaining endothelium integrity and repairing its damage (145). Increasing evidence suggests that EPC may originate from several bone marrow cell populations. According to the initial description, EPCs are defined as cells expressing both hematopoietic stem cell markers, such as CD34 and CD133, and endothelial markers such as vascular endothelail growth factor receptor-2 and Tie-2 (4, 49, 59). Other reports suggest that myelo/monocytic cells can give rise to endothelial cells as well, especially the CD14+/CD34– myeloid cell population (131, 146). In addition, a subset of mesenchymal stem cells (termed multipotent adult progenitor cells) has the ability to differentiate into multiple cells types, including mature, functional endothelial cells (80, 123). They may represent a unique subset of EPCs. The above bone marrow-derived EPC can home to sites of ischemia and to damaged vessels. Infusion of EPCs was shown to augment capillary density and neovascularization of ischemic tissues, including infarcted myocardium (4, 85, 116), ischemic limbs (4, 5), or brain (162). Emerging evidence indicates that EPCs may play a critical role in the maintenance of intact vascular endothelium and in the repair of endothelial injury through the process of reendothelization as exemplified by atherosclerotic lesions (107, 121), direct mechanical injury to the endothelium (77), as well as inflammatory damage (158).

The balance between injury and repair is a life-long, carefully guarded process. The activation of local resident stem cells or the recruitment of circulating stem and progenitor cells may be a very important event during this process. A recent report indicated that early display of age-related endothelial dysfunction may be more strongly correlated to impaired EPC activity rather than decreased number when healthy young and old individuals were compared (63). Nonetheless, a study in the healthy individuals who bear cardiovascular risk factors has revealed a strong correlation between the number of circulation EPCs and the subjects' combined Framingham risk factor score and the endothelial function (66). EPC level is suggested to be a surrogate biological marker for vascular function and cumulative cardiovascular risk.

Like any other cell type, EPCs are subjected to various stressors that could impair their function and proliferative capability. Circulating EPCs in healthy smokers exhibit impaired functional activities (66, 105). Hyperglycemia has been reported to reduce survival and impair function of EPCs (86). There is growing evidence that senescence may serve as an important mechanism mediating EPC dysfunction. Decreased numbers and an increased proportion of senescent EPC has been reported in patients with preeclampsia (141). Accelerated EPC senescence has also been noted in both experimental hypertensive rats and patients with essential hypertension (66, 75). Angiotensin II can induce EPC senescence through the induction of oxidative stress and influence telomerase activity (72). Oxidized low-density lipoprotein induces EPC senescence and leads to cellular dysfunction (74). EPCs from Type II diabetics exhibit impaired proliferation, adhesion, and engraftment in vascular structures (142). Except all of the pathophysiological conditions mentioned above, EPC dysfunction has also been documented in Type I diabetes (95, 142), coronary artery disease (148, 155), atherosclerosis (107, 121), rheumatoid arthritis (54, 65), vasculitis with kidney involvement (69), and end-stage renal disease (27, 36).


   DIABETIC VASCULOPATHY AND SENESCENCE
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 
Even though the role of cell senescence in vascular biology remains underdeveloped, the adverse effects of endothelial SIPS appear to be obvious: the rapid development of macro- and microangiopathy as has been suggested by our recent studies and discussed briefly below.

Diabetic microvascular and macrovascular injury is central to the development of renal, retinal, neurological, and cardiovascular complications (22). In the early pathogenesis of diabetes, hyperglycemia perturbs several key vascular endothelial functions, leading to endothelial cell dysfunction, which is intimately linked to the impaired balance of the L-arginine-eNOS-NO system (52). These vascular alterations are thought to be of relevance to the onset and progression of diabetic complications (68, 114, 125).

Among the several proposed underlying mechanisms for hyperglycemia-induced vascular damage, evidence indicates a major role for increased advanced glycation end-products (AGEs). formation (29, 90, 132, 153). AGE precursors arise from the nonenzymatic reactions between glucose/glucose-derived dicarbonyls and cellular proteins, known collectively as Maillard reactions, which represent a series of reactions of rearrangement, dehydration, oxidation, and fragmentation of glucose or its adducts to protein (9). As a result of its chemical and structural alteration (62), AGEs cause excessive cytotoxic stress to the vascular system. In endothelial cells exposed to high glucose, intracellular AGE formation can occur within a week. In long-living tissue proteins, like collagen, AGE will accumulate over time at a rate that correlates with the protein half-life. During diabetes, AGEs are formed at an accelerating rate (157) resulting in very high tissue levels (23, 70).

We have examined the contribution of endothelial cell senescence to the pathogenesis of diabetic vasculopathy by using a glycated collagen I (GC)/endothelial cell culture system (30). We found that the senescent phenotype can be induced in early-passage HUVEC when cultured on a glycated matrix protein collagen I. An increased frequency of prematurely senescent cells, as judged by the presence of SA-beta gal and overexpression of p53, p21, and p16, was similarly observed in the endothelium of aortas from 22-wk-old Zucker diabetic fat (ZDF) rats compared to Zucker lean (ZL) controls (Fig. 3, A and B).


Figure 3
View larger version (88K):
[in this window]
[in a new window]
  		Fig. 3. Vignettes illustrating the extent and mechanisms of vasculopathy in Zucker diabetic fatty rats and the results of treatment with ebselen (Ebs, E). A: en face view of SA-beta-galactosidase expression by the aortic endothelium in 22-wk-old Zucker diabetic fatty rats and prevention of endothelial cell senescence with chronic ebselen treatment. B: thoracic aortic cross-sections and the expression of p53, p16, and p21 by endothelial cells. Representative images obtained from 22-wk-old ZL, ZDF, and ZDF + ebselen rat aortas. C: functional characteristics of prematurely senescent vasculature (a, diminished NO production; b, impaired vasorelaxation; c, maintenance of total pterin levels and reduction of tetrahydrobiopterin level). For NO production and aorta relaxation levels (Ca and Cb): *P < 0.05 vs. ZL 22w, ZL 22w +E, and ZDF 22w + E; #P < 0.05 vs. ZDF 22w. For BH2 levels (Cc): *P < 0.05 vs. 8-wk-old ZL rats; **P < 0.01 vs. 22-wk-old ZL rats; ***P < 0.01 vs. 22-wk-old ZDF rats. For BH4 levels (Cc): #P < 0.05 vs. 22-wk-old ZL rats; ##P < 0.05 vs. 22-wk-old ZDF rats. Compiled and modified from Brodsky et al. (18) and Chander et al. (28).

 
Separate experiments were performed to quantify the number of senescent endothelial cells in the aorta and correlate it with parameters characteristic of endothelial dysfunction, including the measurement of NO production, the vascular reactivity to acetylcholine, abundance of endothelial microparticles in the circulation, and the angiogenic competence of various vascular beds (18, 28, 48). Our results indicate that accumulation of senescent endothelial cells in the aorta of 16- to 22-wk-old ZDF rats is accompanied by reduced NO production and severely impaired acetylcholine-induced vasorelaxation (Fig. 3C, left and middle). The ability to form collateral blood vessels after femoral artery ligation is also noticeably reduced as assessed by laser Doppler flowmetry/imaging and histochemical detection of the capillary density in the affected striated muscle (18). Similar results were obtained by an ex vivo angiogenesis assay (19).

The development of microvasculopathy was also evaluated in the kidney of ZDF rats. At 22 wk of age, these animals developed proteinuria and a reduced creatinine clearance. Histological assessment showed that both the glomeruloscerosis and tubulointerstitial scarring index increased and focal segmental glomerulosclerosis was observed in 9.5 ± 1.8% glomeruli. Oil-Red-O staining revealed widespread lipid deposits (28, 47). Immunodetectable 3NT, a footprint of peroxynitrite formation and oxidative stress (28, 30), as well as immunodetectable lipid peroxides, were both significantly elevated in tissues of 22-wk-old ZDF rats compared to age-matched ZL rats. The levels of glutathione and tetrahydrobiopterin in the renal tissue were markedly reduced in 22-wk-old ZDF (Fig. 3C, right). Collectively, these findings are indicative of oxidative and nitrosative stress in ZDF rats, operant at 22 wk, in the tubules, glomeruli, and throughout the vascular tree, particularly the endothelium.


   THERAPEUTIC HORIZONS
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
GRANTS
 REFERENCES
 
The so-called anti-aging therapy would be, at least conceptually, aimed at "reversing age-related changes... and decelerating or preventing aging changes" (57). In practice, the approaches that are being proposed to modulate aging in a wide variety of organisms commonly bear the ultimate aim of improving the quality of human life in old age. The approaches that have been tested include gene therapy, stem cell transfusion, hormonal supplementation, nutritional modulation, and intervention by antioxidants and other molecules (55, 98, 120).

On the basis of studies of aging, cellular senescence, and calorie restriction (the only experimental manipulation that is know to extend the lifespan of a number of organisms), several genes have been tested for gene therapy. These genes include, but are not limited to, the following: the DNA-associated proteins, such as Rad51 and Rad54, which may provide more efficient gene repair in human cells (94); the p66shc gene, which controls the production of reactive oxygen species (ROS) (106); the reverse transcriptase protein component of telomerase (hTERT), which has served as either a gene for transducing targeted cells, or a targeted antigen itself for cancer immunotherapy (102, 127, 134, 150); the Sirt1 gene, a mammalian homology of SIR2 that encodes an NAD-dependent deacetylase in yeast and may mediate the effects of calorie restriction (15, 56).

Given the unique abilities of stem cells to self-renew, differentiate, and proliferate, they are critically important to an organism not only during development but also for homeostasis. The anticipated therapeutic potential of utilizing stem cells for the treatment of many chronic human diseases has created much attention. The feasibility of the strategy of stem cell transfusion has been tested with many promising results reported (11, 13, 109, 126, 130). Some investigators have been trying to preserve the endothelial progenitor cell population from early onset of senescence by using, for instance, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition (statins) or estrogen (6, 73, 140). Detailed analysis of these strategies is beyond the scope of this review, and interested readers are referred to the excellent reviews mentioned above. In the following, we focus our discussion on antioxidant therapy and summarize some of our in vitro and in vivo study results related to this strategy.

Whereas in short-lived species, antioxidant treatment has been successful in prolonging lifespan (83), this has not been the case in mammals. The lifespan was unchanged in middle-age mice receiving lipoic acid or coenzyme Q10 antioxidant supplements but increased by 13% in mice receiving caloric restriction (91). Antioxidant therapy was reported to be ineffective in prolonging the lifespan in mammalian model systems, but there is evidence that antioxidant treatment protects against age-related dysfunction, including cognitive decline, as discussed in a recent review (51). On the other hand, targeted mutation of mouse p66shc gene, which controls the production of ROS, induces resistance to stress and a 30% increase in lifespan. Improvement of vascular function in p66shc ablated aging mice has been observed, and the p53/p21 stress response pathway is impaired in p66shc–/– cells (106). The deletion of p66shc was shown to reduce systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet (112). In this regard, it is intriguing to note that calorie restriction can also increase the resistance to oxidative stress (139), which is believed to contribute to the beneficial outcomes of calorie restriction.

Senescence has been classically viewed as a state of permanent growth arrest, and hence cells are rendered unable to re-enter the cell cycle. Though this concept is still widely accepted, recent studies have provided evidence indicating that under certain conditions senescence is reversible, at least in the early stages. Stable suppression of p53 expression in senescent mouse embryo fibroblasts through RNA interference leads to rapid cell cycle re-entry and to immortalization, indicating that both initiation and maintenance of senescence is p53 dependent (6). In a separate experiment, senescent human fibroblasts and mammary epithelial cells with low levels of p16 resumed robust growth after inactivation of p53, whereas those with high levels of p16 remained senescent. Exogenous expression of oncogenic ras can also induce limited growth in the same low p16 level senescent cell population (10). Caveolin-1 reduction, using an antisense and small interfering RNA strategy, can also induce senescent human fibroblasts to re-enter cell cycle upon epidermal growth factor stimulation (35).

We have tested the hypothesis that premature endothelial cell senescence is not only preventable but also reversible. Based on the finding of enhanced peroxynitrite formation in aging and stressed vasculature (30, 147), we performed a series of in vitro and in vivo experiments addressing the effect of a bona fide peroxynitrite scavenger and antioxidant ebselen. This seleno-organic compound scavenging peroxynitrite (99) was able to prevent and reverse senescence of early-passage HUVECs and preserve functional activity of eNOS in vitro by scavenging peroxynitrite (18, 30). The ability to prevent and reverse vascular dysfunction was tested in vivo by treating ZDF rats with ebselen between the ages of 8 to 22 wk (treatment initiated when the hyperglycemia has just developed), 13 to 22 wk, or 16 to 22 wk (treatment initiated when vasculopathy was already present) (18, 28, 47). Our results indicate that ebselen cannot only prevent macro- and microvasculopathy in Zucker diabetic fatty rats when administered from weeks 8 to 22 but partially reverses vasculopathy when administered from weeks 13 to 22 (i.e., starting shortly after the early onset of vasculopathy). This was accompanied by the prevention and reversal of endothelial cell senescence in the aorta. The above effects either diminish or disappear when administration of ebselen starts at week 16 and lasts until 22 wk of age in Zucker diabetic fatty rats.

Macro- and microvascular complications of metabolic syndrome and diabetes are among leading causes of morbidity and mortality. Tight glucose control alone is insufficient to prevent macrovasculopathy, but there are indications that the soluble extracellular portion of the AGE receptor or AGE "breakers" are capable of preventing these complications (154). Notably, both agents are acting on the upstream, prereceptor mechanisms of endothelial dysfunction. Ebselen therapy, on the other hand, targets downstream, postreceptor cellular consequences of endothelial oxidative stress. One of the possible attractive features of selenorganic compounds is their combined peroxynitrite scavenging and antioxidant effect (99), thus, potentially not only preventing further oxidant stress, but also accelerating the clearance of preformed 3-NT-modified proteins. Indeed, the fact that ebselen not only prevents, but also reverses, the preexisting vasculopathy makes it a promising therapeutic agent.


   GRANTS
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
REFERENCES
 
Studies presented here were supported in part by National Institutes of Health Grants DK-45462, DK-54602, DK-52783 (to M. S. Goligorsky) and by American Heart Association Young Investigator Award 0430255N (to J. Chen).


   ACKNOWLEDGMENTS
 
We thank Dr. Edmond O'Riordan and Dr. Matthew Plotkin for reading and invaluable suggestions.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Chen or M. S. Goligorsky, Depts. of Medicine and Pharmacology, Renal Research Institute, ew York Medical College, Valhalla, NY 10595 (email: jun_chen{at}nymc.edu or Michael_goligorsky{at}nymc.edu)


   REFERENCES
TOP
 ABSTRACT
 HISTORY OF SENESCENCE RESEARCH
 REGULATION OF SENESCENCE
 RELATION BETWEEN SENESCENCE AND...
 LYSOSOMAL-MITOCHONDRIAL...
 SENESCENCE AND DISEASES
 DIABETIC VASCULOPATHY AND...
 THERAPEUTIC HORIZONS
 GRANTS
 REFERENCES
 

  1. Abe A, Gregory S, Lee L, and Shayman JA. Use of sulfobutyl ether beta-cyclodextrin as a vehicle for D-threo-1-phenyl-2-decanoylamino-3-morpholinopropanol-relat ed glucosylceramide synthase inhibitors. Anal Biochem 287: 344–347, 2000.[CrossRef][Web of Science][Medline]
  2. Anes E, Kuhnel MP, Bos E, Moniz-Pereira J, Habermann A, and Griffiths G. Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria. Nat Cell Biol 5: 793–802, 2003. Epub 2003 Aug 24.[CrossRef][Web of Science][Medline]
  3. Artandi SE and DePinho RA. A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr Opin Genet Dev 10: 39–46, 2000.[CrossRef][Web of Science][Medline]
  4. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, and Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967, 1997.[Abstract/Free Full Text]
  5. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, and Isner JM. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18: 3964–3972, 1999.[CrossRef][Web of Science][Medline]
  6. Assmus B, Urbich C, Aicher A, Hofmann WK, Haendeler J, Rossig L, Spyridopoulos I, Zeiher AM, and Dimmeler S. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res 92: 1049–1055, 2003. Epub 2003 Apr 3.[Abstract/Free Full Text]
  7. Balin AK, Fisher AJ, Anzelone M, Leong I, and Allen RG. Effects of establishing cell cultures and cell culture conditions on the proliferative life span of human fibroblasts isolated from different tissues and donors of different ages. Exp Cell Res 274: 275–287, 2002.[CrossRef][Web of Science][Medline]
  8. Balin AK, Pratt L, and Allen RG. Effects of ambient oxygen concentration on the growth and antioxidant defenses of of human cell cultures established from fetal and postnatal skin. Free Radic Biol Med 32: 257–267, 2002.[CrossRef][Web of Science][Medline]
  9. Baynes JW. The role of AGEs in aging: causation or correlation. Exp Gerontol 36: 1527–1537, 2001.[CrossRef][Web of Science][Medline]
  10. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, and Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22: 4212–4222, 2003.[CrossRef][Web of Science][Medline]
  11. Bell DR and Van Zant G. Stem cells, aging, and cancer: inevitabilities and outcomes. Oncogene 23: 7290–7296, 2004.[CrossRef][Web of Science][Medline]
  12. Ben-Porath I and Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37: 961–976, 2005. Epub 2004 Dec 30.[CrossRef][Web of Science][Medline]
  13. Bernal GM and Peterson DA. Neural stem cells as therapeutic agents for age-related brain repair. Aging Cell 3: 345–351, 2004.[CrossRef][Web of Science][Medline]
  14. Bladier C, Wolvetang EJ, Hutchinson P, de Haan JB, and Kola I. Response of a primary human fibroblast cell line to H2O2: senescence-like growth arrest or apoptosis? Cell Growth Differ 8: 589–598, 1997.[Abstract]
  15. Bordone L and Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6: 298–305, 2005.[CrossRef][Web of Science][Medline]
  16. Breitschopf K, Zeiher AM, and Dimmeler S. Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism. FEBS Lett 493: 21–25, 2001.[CrossRef][Web of Science][Medline]
  17. Bringold F and Serrano M. Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 35: 317–329, 2000.[CrossRef][Web of Science][Medline]
  18. Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A, and Goligorsky MS. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res 94: 377–384, 2004. Epub 2003 Dec 11.[Abstract/Free Full Text]
  19. Brodsky SV, Smith M, Kashgarian M, and Goligorsky MS. A model for ex vivo renal angiogenesis. Nephron Exp Nephrol 93: e46–e52, 2003.[CrossRef][Medline]
  20. Brookes S, Rowe J, Gutierrez Del Arroyo A, Bond J, and Peters G. Contribution of p16(INK4a) to replicative senescence of human fibroblasts. Exp Cell Res 298: 549–559, 2004.[CrossRef][Web of Science][Medline]
  21. Brookes S, Rowe J, Ruas M, Llanos S, Clark PA, Lomax M, James MC, Vatcheva R, Bates S, Vousden KH, Parry D, Gruis N, Smit N, Bergman W, and Peters G. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 21: 2936–2945, 2002.[CrossRef][Web of Science][Medline]
  22. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820, 2001.[CrossRef][Medline]
  23. Brownlee M, Cerami A, and Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318: 1315–1321, 1988.[Web of Science][Medline]
  24. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11: S27–S31, 2001.[Web of Science][Medline]
  25. Campisi J. The role of cellular senescence in skin aging. J Investig Dermatol Symp Proc 3: 1–5, 1998.[Medline]
  26. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522, 2005.[CrossRef][Web of Science][Medline]
  27. Chan CT, Li SH, and Verma S. Nocturnal hemodialysis is associated with restoration of impaired endothelial progenitor cell biology in end-stage renal disease. Am J Physiol Renal Physiol 289: F679–F684, 2005. First published May 31, 2005; doi:10.1152/ajprenal.00127.2005.[Abstract/Free Full Text]
  28. Chander PN, Gealekman O, Brodsky SV, Elitok S, Tojo A, Crabtree M, Gross SS, and Goligorsky MS. Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: prevention by chronic therapy with a peroxynitrite scavenger ebselen. J Am Soc Nephrol 15: 2391–2403, 2004.[Abstract/Free Full Text]
  29. Chappey O, Dosquet C, Wautier MP, and Wautier JL. Advanced glycation end products, oxidant stress and vascular lesions. Eur J Clin Invest 27: 97–108, 1997.[CrossRef][Web of Science][Medline]
  30. Chen J, Brodsky SV, Goligorsky DM, Hampel DJ, Li H, Gross SS, and Goligorsky MS. Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. Circ Res 90: 1290–1298, 2002.[Abstract/Free Full Text]
  31. Chen Q and Ames BN. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA 91: 4130–4134, 1994.[Abstract/Free Full Text]
  32. Chen QM. Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints. Ann NY Acad Sci 908: 111–125, 2000.[Web of Science][Medline]
  33. Chen QM, Liu J, and Merrett JB. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. Biochem J 347: 543–551, 2000.[CrossRef][Web of Science][Medline]
  34. Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, and Anversa P. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 93: 604–613, 2003. Epub 2003 Sep 4.[Abstract/Free Full Text]
  35. Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, and Park SC. Senescent phenotype can be reversed by reduction of caveolin status. J Biol Chem 278: 27789–27795, 2003. Epub May 1, 2003.[Abstract/Free Full Text]
  36. Choi JH, Kim KL, Huh W, Kim B, Byun J, Suh W, Sung J, Jeon ES, Oh HY, and Kim DK. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 24: 1246–1252, 2004.[Abstract/Free Full Text]
  37. Comi P, Chiaramonte R, and Maier JA. Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells. Exp Cell Res 219: 304–308, 1995.[CrossRef][Web of Science][Medline]
  38. Dagarag M, Evazyan T, Rao N, and Effros RB. Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J Immunol 173: 6303–6311, 2004.[Abstract/Free Full Text]
  39. Dannenberg JH, van Rossum A, Schuijff L, and te Riele H. Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14: 3051–3064, 2000.[Abstract/Free Full Text]
  40. Deng Q, Liao R, Wu BL, and Sun P. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J Biol Chem 279: 1050–1059, 2004. Epub Oct 29, 2003.[Abstract/Free Full Text]
  41. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, and Campisi J. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363–9367, 1995.[Abstract/Free Full Text]
  42. Drayton S and Peters G. Immortalisation and transformation revisited. Curr Opin Genet Dev 12: 98–104, 2002.[CrossRef][Web of Science][Medline]
  43. Effros RB. Insights on immunological aging derived from the T lymphocyte cellular senescence model. Exp Gerontol 31: 21–27, 1996.[CrossRef][Web of Science][Medline]
  44. Famulski KS and Halloran PF. Molecular events in kidney ageing. Curr Opin Nephrol Hypertens 14: 243–248, 2005.[Web of Science][Medline]
  45. Fenton M, Barker S, Kurz DJ, and Erusalimsky JD. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol 21: 220–226, 2001.[Abstract/Free Full Text]
  46. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, and Lowe SW. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol 22: 3497–3508, 2002.[Abstract/Free Full Text]
  47. Gealekman O, Brodsky SV, Zhang F, Chander PN, Friedli C, Nasjletti A, and Goligorsky MS. Endothelial dysfunction as a modifier of angiogenic response in Zucker diabetic fat rat: amelioration with Ebselen. Kidney Int 66: 2337–2347, 2004.[CrossRef][Web of Science][Medline]
  48. Gealekman O, Brodsky SV, Zhang F, Chander PN, Friedli C, Nasjletti A, Goligorsky MS, Elitok S, Tojo A, Crabtree M, Gross SS, Chen J, and Togashi N. Endothelial dysfunction as a modifier of angiogenic response in Zucker diabetic fat rat: amelioration with Ebselen. Kidney Int 66: 2337–2347, 2004.[CrossRef][Web of Science][Medline]
  49. Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M, Schuch G, Schafhausen P, Mende T, Kilic N, Kluge K, Schafer B, Hossfeld DK, and Fiedler W. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 95: 3106–3112, 2000.[Abstract/Free Full Text]
  50. Gire V, Roux P, Wynford-Thomas D, Brondello JM, and Dulic V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 23: 2554–2563, 2004. Epub Jun 10, 2004.[CrossRef][Web of Science][Medline]
  51. Golden TR, Hinerfeld DA, and Melov S. Oxidative stress and aging: beyond correlation. Aging Cell 1: 117–123, 2002.[CrossRef][Web of Science][Medline]
  52. Goligorsky MS. Endothelial cell dysfunction and nitric oxide synthase. Kidney Int 58: 1360–1376, 2000.[CrossRef][Web of Science][Medline]
  53. Gorbunova V, Seluanov A, and Pereira-Smith OM. Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. J Biol Chem 277: 38540–38549, 2002. Epub Jul 24 2002.[Abstract/Free Full Text]
  54. Grisar J, Aletaha D, Steiner CW, Kapral T, Steiner S, Seidinger D, Weigel G, Schwarzinger I, Wolozcszuk W, Steiner G, and Smolen JS. Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis. Circulation 111: 204–211, 2005. Epub Jan 10, 2005.[Abstract/Free Full Text]
  55. Grossman T. Latest advances in antiaging medicine. Keio J Med 54: 85–94, 2005.[CrossRef][Medline]
  56. Guarente L and Picard F. Calorie restriction–the SIR2 connection. Cell 120: 473–482, 2005.[CrossRef][Web of Science][Medline]
  57. Hadley EC, Lakatta EG, Morrison-Bogorad M, Warner HR, and Hodes RJ. The future of aging therapies. Cell 120: 557–567, 2005.[CrossRef][Web of Science][Medline]
  58. Hampel B, Malisan F, Niederegger H, Testi R, and Jansen-Durr P. Differential regulation of apoptotic cell death in senescent human cells. Exp Gerontol 39: 1713–1721, 2004.[CrossRef][Web of Science][Medline]
  59. Handgretinger R, Gordon PR, Leimig T, Chen X, Buhring HJ, Niethammer D, and Kuci S. Biology and plasticity of CD133+ hematopoietic stem cells. Ann NY Acad Sci 996: 141–151, 2003.[Web of Science][Medline]
  60. Harley CB, Futcher AB, and Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460, 1990.[CrossRef][Medline]
  61. Hayflick L and Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585–621, 1961.[CrossRef][Web of Science][Medline]
  62. Heidland A, Sebekova K, and Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis 38: S100–S106, 2001.[Web of Science][Medline]
  63. Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, and Kalka C. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 45: 1441–1448, 2005.[Abstract/Free Full Text]
  64. Herbig U, Jobling WA, Chen BP, Chen DJ, and Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14: 501–513, 2004.[CrossRef][Web of Science][Medline]
  65. Herbrig K, Haensel S, Oelschlaegel U, Pistrosch F, Foerster S, and Passauer J. Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells. Ann Rheum Dis 23: 23, 2005.
  66. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, and Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348: 593–600, 2003.[Abstract/Free Full Text]
  67. Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM, and Dimmeler S. Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res 89: 709–715, 2001.[Abstract/Free Full Text]
  68. Hofmann MA, Kohl B, Zumbach MS, Borcea V, Bierhaus A, Henkels M, Amiral J, Schmidt AM, Fiehn W, Ziegler R, Wahl P, and Nawroth PP. Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care 21: 841–848, 1998.[Abstract]
  69. Holmen C, Elsheikh E, Stenvinkel P, Qureshi AR, Pettersson E, Jalkanen S, and Sumitran-Holgersson S. Circulating inflammatory endothelial cells contribute to endothelial progenitor cell dysfunction in patients with vasculitis and kidney involvement. J Am Soc Nephrol 16: 3110–3120, 2005. Epub Aug 17, 2005.[Abstract/Free Full Text]
  70. Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, van Ypersole de Strihou C, Monnier VM, Witztum JL, and Kurokawa K. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 100: 2995–3004, 1997.[Web of Science][Medline]
  71. Ihling C, Menzel G, Wellens E, Monting JS, Schaefer HE, and Zeiher AM. Topographical association between the cyclin-dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue. Arterioscler Thromb Vasc Biol 17: 2218–2224, 1997.[Abstract/Free Full Text]
  72. Imanishi T, Hano T, and Nishio I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens 23: 97–104, 2005.[CrossRef][Web of Science][Medline]
  73. Imanishi T, Hano T, and Nishio I. Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells. Hypertens Res 28: 263–271, 2005.[CrossRef][Web of Science][Medline]
  74. Imanishi T, Hano T, Sawamura T, and Nishio I. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin Exp Pharmacol Physiol 31: 407–413, 2004.[CrossRef][Web of Science][Medline]
  75. Imanishi T, Moriwaki C, Hano T, and Nishio I. Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension. J Hypertens 23: 1831–1837, 2005.[Web of Science][Medline]
  76. Itahana K, Campisi J, and Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5: 1–10, 2004.[CrossRef][Web of Science][Medline]
  77. Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, Isner JM, Asahara T, and Losordo DW. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 108: 3115–3121, 2003. Epub Dec 3115, 2003.[Abstract/Free Full Text]
  78. Jacobs JJ and de Lange T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol 14: 2302–2308, 2004.[CrossRef][Web of Science][Medline]
  79. Jarrard DF, Sarkar S, Shi Y, Yeager TR, Magrane G, Kinoshita H, Nassif N, Meisner L, Newton MA, Waldman FM, and Reznikoff CA. p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells. Cancer Res 59: 2957–2964, 1999.[Abstract/Free Full Text]
  80. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, and Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418: 41–49, 2002. Epub Jun 2020, 2002.[CrossRef][Medline]
  81. Joosten SA, van Ham V, Nolan CE, Borrias MC, Jardine AG, Shiels PG, van Kooten C, and Paul LC. Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. Am J Pathol 162: 1305–1312, 2003.[Abstract/Free Full Text]
  82. Kaneko T, Tahara S, Taguchi T, and Kondo H. Accumulation of oxidative DNA damage, 8-oxo-2'-deoxyguanosine, and change of repair systems during in vitro cellular aging of cultured human skin fibroblasts. Mutat Res 487: 19–30, 2001.[Web of Science][Medline]
  83. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 120: 449–460, 2005.[CrossRef][Web of Science][Medline]
  84. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, and Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396: 84–88, 1998.[CrossRef][Medline]
  85. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, and Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7: 430–436, 2001.[CrossRef][Web of Science][Medline]
  86. Krankel N, Adams V, Linke A, Gielen S, Erbs S, Lenk K, Schuler G, and Hambrecht R. Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 25: 698–703, 2005. Epub Jan 2020, 2005.[Abstract/Free Full Text]
  87. Kulju KS and Lehman JM. Increased p53 protein associated with aging in human diploid fibroblasts. Exp Cell Res 217: 336–345, 1995.[CrossRef][Web of Science][Medline]
  88. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, and Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 117: 2417–2426, 2004.[Abstract/Free Full Text]
  89. Kyriakis JM and Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81: 807–869, 2001.[Abstract/Free Full Text]
  90. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, and Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272: 17810–17814, 1997.[Abstract/Free Full Text]
  91. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, and Prolla TA. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 36: 1043–1057, 2004.[CrossRef][Web of Science][Medline]
  92. Lee L, Abe A, and Shayman JA. Improved inhibitors of glucosylceramide synthase. J Biol Chem 274: 14662–14669, 1999.[Abstract/Free Full Text]
  93. Liu JP. Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB J 13: 2091–2104, 1999.[Abstract/Free Full Text]
  94. Liu L, Parekh-Olmedo H, and Kmiec EB. The development and regulation of gene repair. Nat Rev Genet 4: 679–689, 2003.[Web of Science][Medline]
  95. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, and van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53: 195–199, 2004.[Abstract/Free Full Text]
  96. MacLaren A, Black EJ, Clark W, and Gillespie DA. c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation. Mol Cell Biol 24: 9006–9018, 2004.[Abstract/Free Full Text]
  97. Maier JA, Statuto M, and Ragnotti G. Senescence stimulates U937-endothelial cell interactions. Exp Cell Res 208: 270–274, 1993.[CrossRef][Web of Science][Medline]
  98. Malavolta M, Mocchegiani E, and Bertoni-Freddari C. New trends in biomedical aging research. Gerontology 50: 420–424, 2004.[CrossRef][Web of Science][Medline]
  99. Masumoto H, Kissner R, Koppenol WH, and Sies H. Kinetic study of the reaction of ebselen with peroxynitrite. FEBS Lett 398: 179–182, 1996.[CrossRef][Web of Science][Medline]
  100. Mathon NF and Lloyd AC. Cell senescence and cancer. Nat Rev Cancer 1: 203–213, 2001.[CrossRef][Medline]
  101. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, and Tsao PS. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ Res 89: 793–798, 2001.[Abstract/Free Full Text]
  102. Mattson MP. Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy. Exp Gerontol 35: 489–502, 2000.[CrossRef][Web of Science][Medline]
  103. Mayer B and Oberbauer R. Mitochondrial regulation of apoptosis. News Physiol Sci 18: 89–94, 2003.[Abstract/Free Full Text]
  104. Melk A and Halloran PF. Cell senescence and its implications for nephrology. J Am Soc Nephrol 12: 385–393, 2001.[Free Full Text]
  105. Michaud SE, Dussault S, Haddad P, Groleau J, and Rivard A. Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities. Atherosclerosis 7: 7, 2005.
  106. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, and Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309–313, 1999.[CrossRef][Medline]
  107. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, and Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105: 1541–1544, 2002.[Abstract/Free Full Text]
  108. Minamino T, Miyauchi H, Yoshida T, Tateno K, Kunieda T, and Komuro I. Vascular cell senescence and vascular aging. J Mol Cell Cardiol 36: 175–183, 2004.[CrossRef][Web of Science][Medline]
  109. Nagai T, Shiojima I, Matsuura K, and Komuro I. Promotion of cardiac regeneration by cardiac stem cells. Circ Res 97: 615-617, 2005.[Free Full Text]
  110. Naka K, Tachibana A, Ikeda K, and Motoyama N. Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. J Biol Chem 279: 2030–2037, 2004. Epub 2003 Oct 21.[Abstract/Free Full Text]
  111. Nakajima M, Hashimoto M, Wang F, Yamanaga K, Nakamura N, Uchida T, and Yamanouchi K. Aging decreases the production of PGI2 in rat aortic endothelial cells. Exp Gerontol 32: 685–693, 1997.[CrossRef][Web of Science][Medline]
  112. Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, and Pelicci P. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA 100: 2112–2116, 2003. Epub 2003 Feb 2115.[Abstract/Free Full Text]
  113. Narita M, Nunez S, Heard E, Lin AW, Hearn SA, Spector DL, Hannon GJ, and Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113: 703–716, 2003.[CrossRef][Web of Science][Medline]
  114. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, and Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404: 787–790, 2000.[CrossRef][Medline]
  115. Ogryzko VV, Hirai TH, Russanova VR, Barbie DA, and Howard BH. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol 16: 5210–5218, 1996.[Abstract]
  116. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, and Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98: 10344–10349, 2001. Epub 2001 Aug 14.[Abstract/Free Full Text]
  117. Palmero I and Serrano M. Induction of senescence by oncogenic Ras. Methods Enzymol 333: 247–256, 2001.[CrossRef][Web of Science][Medline]
  118. Parrinello S, Coppe JP, Krtolica A, and Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118: 485–49, 20056. Epub 2005 Jan 18.[Abstract/Free Full Text]
  119. Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, and Campisi J. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5: 741–747, 2003.[CrossRef][Web of Science][Medline]
  120. Rattan SI. Aging, anti-aging, and hormesis. Mech Ageing Dev 125: 285–289, 2004.[CrossRef][Web of Science][Medline]
  121. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, and Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 108: 457–463, 2003. Epub 2003 Jul 14.[Abstract/Free Full Text]
  122. Rebbaa A, Zheng X, Chou PM, and Mirkin BL. Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene 22: 2805–2811, 2003.[CrossRef][Web of Science][Medline]
  123. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, and Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109: 337–346, 2002.[CrossRef][Web of Science][Medline]
  124. Rincheval V, Renaud F, Lemaire C, Godefroy N, Trotot P, Boulo V, Mignotte B, and Vayssiere JL. Bcl-2 can promote p53-dependent senescence versus apoptosis without affecting the G1/S transition. Biochem Biophys Res Commun 298: 282–288, 2002.[CrossRef][Web of Science][Medline]
  125. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, and Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev 17: 189–212, 2001.[CrossRef][Web of Science][Medline]
  126. Rosenthal N. Youthful prospects for human stem-cell therapy. In another few decades, revised attitudes toward stem cells could lead to disease prevention and life extension. EMBO Rep 6: S30–S34, 2005.[CrossRef][Web of Science][Medline]
  127. Rufer N and Nabholz M. Telomerase, elixir of life for human cells? Med Sci 19: 345–350, 2003.
  128. Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E, and Jacks T. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev 14: 3037–3050, 2000.[Abstract/Free Full Text]
  129. Sato I, Morita I, Kaji K, Ikeda M, Nagao M, and Murota S. Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. Biochem Biophys Res Commun 195: 1070–1076, 1993.[CrossRef][Web of Science][Medline]
  130. Schatteman GC, Hanlon HD, Jiao C, Dodds SG, and Christy BA. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106: 571–578, 2000.[Web of Science][Medline]
  131. Schmeisser A, Garlichs CD, Zhang H, Eskafi S, Graffy C, Ludwig J, Strasser RH, and Daniel WG. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 49: 671–680, 2001.[Abstract/Free Full Text]
  132. Schmidt AM, Yan SD, Wautier JL, and Stern D. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 84: 489–497, 1999.[Abstract/Free Full Text]
  133. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, and Lowe SW. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109: 335–346, 2002.[CrossRef][Web of Science][Medline]
  134. Schreurs MW, Hermsen MA, Geltink RI, Scholten KB, Brink AA, Kueter EW, Tijssen M, Meijer CJ, Ylstra B, Meijer GA, and Hooijberg E. Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes. Blood 106: 2663–2670, 2005. Epub 2005 Jul 7.[Abstract/Free Full Text]
  135. Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N, and Rotter V. Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol Cell Biol 21: 1552–1564, 2001.[Abstract/Free Full Text]
  136. Serrano M and Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 13: 748–753, 2001.[CrossRef][Web of Science][Medline]
  137. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, and DePinho RA. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413: 86–91, 2001.[CrossRef][Medline]
  138. Shelton DN, Chang E, Whittier PS, Choi D, and Funk WD. Microarray analysis of replicative senescence. Curr Biol 9: 939–945, 1999.[CrossRef][Web of Science][Medline]
  139. Sohal RS and Weindruch R. Oxidative stress, caloric restriction, and aging. Science 273: 59–63, 1996.[Abstract]
  140. Spyridopoulos I, Haendeler J, Urbich C, Brummendorf TH, Oh H, Schneider MD, Zeiher AM, and Dimmeler S. Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation 110: 3136–3142, 2004. Epub 2004 Nov 31.[Abstract/Free Full Text]
  141. Sugawara J, Mitsui-Saito M, Hayashi C, Hoshiai T, Senoo M, Chisaka H, Yaegashi N, and Okamura K. Decrease and senescence of endothelial progenitor cells in patients with preeclampsia. J Clin Endocrinol Metab 90: 5329–5332, 2005. Epub 2005 Jun 14.[Abstract/Free Full Text]
  142. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, and Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106: 2781–2786, 2002.[Abstract/Free Full Text]
  143. Tresini M, Mawal-Dewan M, Cristofalo VJ, and Sell C. A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts. Cancer Res 58: 1–4, 1998.[Abstract/Free Full Text]
  144. Unterluggauer H, Hampel B, Zwerschke W, and Jansen-Durr P. Senescence-associated cell death of human endothelial cells: the role of oxidative stress. Exp Gerontol 38: 1149–1160, 2003.[CrossRef][Web of Science][Medline]
  145. Urbich C and Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95: 343–353, 2004.[Abstract/Free Full Text]
  146. Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, and Dimmeler S. Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation 108: 2511–2516, 2003. Epub 2003 Oct 27.[Abstract/Free Full Text]
  147. van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, and Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192: 1731–1744, 2000.[Abstract/Free Full Text]
  148. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, and Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89: E1–E7, 2001.[Web of Science][Medline]
  149. Volonte D, Zhang K, Lisanti MP, and Galbiati F. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell 13: 2502–2517, 2002.[Abstract/Free Full Text]
  150. Vonderheide RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene 21: 674–679, 2002.[CrossRef][Web of Science][Medline]
  151. Wagner M, Hampel B, Bernhard D, Hala M, Zwerschke W, and Jansen-Durr P. Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis. Exp Gerontol 36: 1327–1347, 2001.[CrossRef][Web of Science][Medline]
  152. Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, and Sun P. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 22: 3389–3403, 2002.[Abstract/Free Full Text]
  153. Wautier JL, Wautier MP, Schmidt AM, Anderson GM, Hori O, Zoukourian C, Capron L, Chappey O, Yan SD, Brett J, Guillausseau PJ, and Stern D. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci USA 91: 7742–7746, 1994.[Abstract/Free Full Text]
  154. Wendt T, Tanji N, Guo J, Hudson BI, Bierhaus A, Ramasamy R, Arnold B, Nawroth PP, Yan SF, D'Agati V, and Schmidt AM. Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 14: 1383–1395, 2003.[Abstract/Free Full Text]
  155. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, and Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353: 999–1007, 2005.[Abstract/Free Full Text]
  156. West MD, Shay JW, Wright WE, and Linskens MH. Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence. Exp Gerontol 31: 175–193, 1996.[CrossRef][Web of Science][Medline]
  157. Wu JT. Advanced glycosylation end products: a new disease marker for diabetes and aging. J Clin Lab Anal 7: 252–255, 1993.[Web of Science][Medline]
  158. Yamada M, Kubo H, Ishizawa K, Kobayashi S, Shinkawa M, and Sasaki H. Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair. Thorax 60: 410–413, 2005.[Abstract/Free Full Text]
  159. Yuan XM, Li W, Dalen H, Lotem J, Kama R, Sachs L, and Brunk UT. Lysosomal destabilization in p53-induced apoptosis. Proc Natl Acad Sci USA 99: 6286–6291, 2002. Epub 2002 Apr 16.[Abstract/Free Full Text]
  160. Zhang H, Pan KH, and Cohen SN. Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc Natl Acad Sci USA 100: 3251–3256, 2003. Epub 2003 Mar 7.[Abstract/Free Full Text]
  161. Zhang J, Patel JM, and Block ER. Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. Mech Ageing Dev 123: 613–625, 2002.[CrossRef][Web of Science][Medline]
  162. Zhang ZG, Zhang L, Jiang Q, and Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 90: 284–288, 2002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
I. T. Struewing, S. N. Durham, C. D. Barnett, and C. D. Mao
Enhanced Endothelial Cell Senescence by Lithium-induced Matrix Metalloproteinase-1 Expression
J. Biol. Chem., June 26, 2009; 284(26): 17595 - 17606.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. Orimo, T. Minamino, H. Miyauchi, K. Tateno, S. Okada, J. Moriya, and I. Komuro
Protective Role of SIRT1 in Diabetic Vascular Dysfunction
Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 889 - 894.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
V. L. Gabai, J. A. Yaglom, T. Waldman, and M. Y. Sherman
Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells
Mol. Cell. Biol., January 15, 2009; 29(2): 559 - 569.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
F. Sanada, Y. Taniyama, J. Azuma, K. Iekushi, N. Dosaka, T. Yokoi, N. Koibuchi, H. Kusunoki, Y. Aizawa, and R. Morishita
Hepatocyte Growth Factor, but not Vascular Endothelial Growth Factor, Attenuates Angiotensin II-Induced Endothelial Progenitor Cell Senescence
Hypertension, January 1, 2009; 53(1): 77 - 82.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
D. A. Ingram, I. Z. Lien, L. E. Mead, M. Estes, D. N. Prater, E. Derr-Yellin, L. A. DiMeglio, and L. S. Haneline
In Vitro Hyperglycemia or a Diabetic Intrauterine Environment Reduces Neonatal Endothelial Colony-Forming Cell Numbers and Function
Diabetes, March 1, 2008; 57(3): 724 - 731.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (15)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, J.
Right arrow Articles by Goligorsky, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, J.
Right arrow Articles by Goligorsky, M. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.