AJP - Heart AJP: Lung Cellular and Molecular Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H1766-H1771, 2007. First published June 15, 2007; doi:10.1152/ajpheart.00017.2007
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/H1766    most recent
00017.2007v1
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 Web of Science
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 Google Scholar
Google Scholar
Right arrow Articles by Westberg, J. A.
Right arrow Articles by Andersson, L. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Westberg, J. A.
Right arrow Articles by Andersson, L. C.

Hypoxic preconditioning induces elevated expression of stanniocalcin-1 in the heart

Johan A. Westberg,1,* Martina Serlachius,1,* Petri Lankila,1 and Leif C. Andersson1,2

1Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland; and 2Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

Submitted 5 January 2007 ; accepted in final form 11 June 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals exposed for a few hours to low oxygen content (8%) develop resistance against further ischemic myocardial damage. The molecular mechanism(s) behind this phenomenon, known as hypoxic preconditioning (HOPC), is still incompletely understood. Stanniocalcin-1 (STC-1) is an evolutionarily conserved glycoprotein originally discovered in fish, in which it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. Our group originally reported expression of mammalian STC-1 in brain neurons and showed that STC-1 is a prosurvival factor that guards neurons against hypercalcemic and hypoxic damage. This study investigates the involvement of STC-1 in HOPC-induced cardioprotection. Wild-type mice and IL-6-deficient (Il-6–/–) mice were kept in hypoxic conditions (8% O2) for 6 h. Myocardial Stc-1 mRNA expression was quantified during hypoxia and after recovery. HOPC triggered a biphasic upregulation of Stc-1 expression in hearts of wild-type mice but not in those of Il-6–/– mice. Treatment of cardiomyocyte cells in culture with hypoxia or IL-6 elicited an Stc-1 response, and ectopically expressed STC-1 in HL-1 cells localized to the mitochondria. Our findings indicate that IL-6-induced expression of STC-1 is one molecular mechanism behind the ischemic tolerance generated by HOPC in the heart.

cardioprotection; interleukin-6; mitochondria

Murry et al. (16) originally demonstrated that ischemic preconditioning (IP) conferred resistance to induced ischemic damage of the myocardium. Hypoxic preconditioning (HOPC), also conferring resistance (13) to further ischemic damage, has been investigated for many years, yet its physiological mechanisms of action remain largely elusive. The development of transiently increased resistance to ischemic tissue damage following IP is dependent on de novo protein synthesis (21) and occurs in a biphasic manner. The first phase develops within minutes and lasts up to a few hours, and the second phase occurs after 12–24 h and lasts for 3–4 days (8, 12, 14).

Hypoxic stress increases the production of IL-6 in the myocardium (32). IL-6 apparently plays an important role, particularly, in the activation of the later phase of elevated resistance to ischemia after preconditioning, since mice with a targeted deletion of the Il-6 gene (Il-6–/–) did not develop cardioprotection after preconditioning (7). Moreover, Smart et al. (27) recently reported that pretreatment with IL-6 significantly increased the survival of neonatal rat cardiomyocytes in a culture subjected to simulated ischemia-reperfusion.

Stanniocalcin-1 (STC-1) is a 56-kDa homodimeric glycoprotein that was first discovered in teleost fish (30), in which it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. STC-1 was considered unique to fish, until the cloning of cDNA for human STC-1 in 1995 (4) and for mouse STC-1 in 1996 (3). STC-1 is evolutionarily highly conserved, with the first 204 amino acids showing 80% similarity between salmon and human STC-1. Mammalian STC-1 is expressed in various organs (36), particularly in tissues containing highly specialized cells with no or limited proliferative capacity, including neural cells, mature adipocytes, megakaryocytes, and heart tissue (for a recent review, see Ref. 24). We originally reported that STC-1 is a prosurvival factor that protects neurons against hypercalcemic and hypoxic damage (37). Moreover, our recent data (31) show that HOPC induces upregulated Stc-1 expression in brain through IL-6 signaling. STC-1 is physiologically expressed in the mammalian myocardium (25). Here, we show that HOPC of mice induces a biphasic upregulation of Stc-1 expression in the heart. We also present in vitro and in vivo findings indicating that IL-6 is a key signaling molecule that contributes to the first peak and is essential for the second peak of elevated Stc-1 expression in the myocardium induced by HOPC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Cell culture and RNA extraction. We cultured the murine cardiomyocyte cell line HL-1 (kindly donated by Dr. W. Claycomb, New Orleans, LA) in supplemented Claycomb medium (6) (JRH Biosciences, Hampshire, UK) in the absence of norepinephrine, due to the ability of norepinephrine to induce IL-6 (32). Cells were maintained at 37°C in a saturated humidity atmosphere containing 95% air-5% CO2. To induce Stc-1 expression, cells were treated with 5 ng/ml IL-6 (R&D Systems, Minneapolis, MN). HL-1 cells were exposed to hypoxic conditions by addition of 20 mM HEPES to the culture medium and maintaining a steady flow of 99.5% nitrogen through the culture flask for 30 min (10). The flasks were sealed and kept at 37°C for 6 h, after which they were areated and returned to normal conditions for an additional 17 or 41 h. Total RNA was isolated by use of TRIZOL reagent (Invitrogen, Carlsbad, CA).

Experimental animals. All procedures involving experimental animals were performed according to institutional and local guidelines. The animal experiments were approved by the National Board for Animal Experiments at The State Provincial Office of Southern Finland (No. ELSH-2006-0584/Ym23. All efforts were made to minimize animal distress and to reduce the number of animals used.

Wild-type (WT) mice were of strain C57BL/6x129SvJ. IL-deficient (Il-6–/–) mice were of strain B6, 129S2-Il6tm1Kopf/J (stock 002254) (Jackson Laboratory, Bar Harbor, ME).

Hypoxia treatment. We subjected mice to hypoxia in a controlled-environment chamber perfused with 8% vol/vol oxygen in nitrogen for 6 h (1, 20, 28, 38), after which they were returned to normal conditions. The mice were killed at 2, 4, and 6 h during the hypoxic period and at 6, 12, 24, 48, and 72 h during recovery. Heart tissue was collected and snap frozen in liquid nitrogen for extraction of total RNA as described above.

Quantitative real-time PCR. We prepared cDNA with the cloned avian myeloblastosis virus first-strand synthesis kit (Invitrogen) and performed quantitative real-time PCR with the Roche LightCycler instrument and the LightCycler FastStart DNA MasterPLUS SYBR green I kit (Roche, Basel, Switzerland). Mouse primers were as follows: Stc-1: 5'-ATGCTCCAAAACTCAGCAGTGATTC-3' and 5'-CAGGCTTCGGACAAGTCTGT-3'; Vegf-a: 5'-GAACTTTCTGCTCTCTTGGG-3' and 5'-TGATGTTGCTCTCTGACGTG-3'. Stc-1 and Vegf-a mRNA were normalized against levels of mouse beta-2-microglobulin (beta2m). Primers were as follows: beta2m: 5'-GCTATCCAGAAAACCCCTCA-3' and 5'-ATGTCTCGATCCCAGTAGAC-3'. All primers were from Proligo (Paris, France).

In situ hybridization. We generated single-stranded antisense and sense RNA probes of a 356-bp mouse Stc-1 cDNA (position 147–502) fragment cloned into the pSPT18 plasmid (Invitrogen). Probes were labeled with digoxigenin-uridine triphosphate by in vitro transcription with SP6 and T7 RNA polymerases according to the manufacturer's instructions (Roche). A sense probe was used as a negative control. Automated hybridization was carried out with a Ventana Discovery Slide Stainer (Ventana Medical Systems, Tucson, AZ). Sections were incubated with monoclonal biotinylated anti-digoxin antibody (Jackson ImmunoResearch Laboratories, West Grove, PA) diluted 1:2,000. The probe was detected with the Ventana Blue Map kit (Ventana Medical Systems).

Immunohistochemistry. Cytospin slides of HL-1 cells, before and after 6 h of hypoxia treatment, were prepared and fixed in acetone. Immunohistochemical stainings were performed with a commercial Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA). The slides were blocked with CAS-Block solution (Zymed Laboratories, San Francisco, CA) for 20 min, followed by incubation overnight at 4°C with rabbit anti-STC antibody (17), diluted 1:1,500 in Chem Mate (Dako, Glostrup, Denmark). The slides were rinsed in three changes of PBS (pH 7.2) between every staining step, and all incubations were carried out in a moist chamber. The peroxidase staining was visualized with 3-amino-9-ethylcarbazole (Sigma, St. Louis, MO) solution (0.2 mg/ml in 0.05 M acetate buffer containing 0.03% perhydrol; pH 5). The slides were counterstained with hematoxylin, washed with distilled water, and mounted in Aquamount (VWR-BDH, West Chester, PA).

Colocalization experiment. HL-1 cells, cultured on coverslips, were transfected with a FLAG-STC-1 construct using Lipofectamine 2000 according to the manufacturer's instructions (Invitrogen). MitoTracker Red CMXRos (Molecular Probes/Invitrogen) was used for the mitochondrial staining of transfected cells. The cells were incubated with 100 nM MitoTracker for 30 min in a 37°C incubator and washed in medium. After fixation in 3.7% paraformaldehyde and permeabilization with 0.2% Triton X-100, the cells were washed in PBS and blocked with swine serum. To detect FLAG-tagged STC-1, the cells were stained with a monoclonal FLAG antibody (5 µg/ml; Sigma) for 1 h, washed, and incubated with goat anti-mouse FITC antibody (Dako) for 30 min.

Data analysis. Data are expressed as means ± SD. We examined the normality of the data and performed all analyses with Student's t-test. P < 0.05 was regarded as statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Exposure of mice to hypoxia induces upregulated expression of STC-1 in the heart. We exposed mice to 8% oxygen for 6 h. After different times of reoxygenation in normal air, we collected heart tissue and quantified Stc-1 mRNA expression. Upregulated expression of Stc-1 mRNA was evident immediately during the period of hypoxia, with a rapid decline to background levels within 6 h of recovery in normoxia. Thereafter, a second phase of increased Stc-1 expression occurred, reaching a maximum at 48 h posthypoxia and declining to control levels at 72 h (Fig. 1A). To put Stc-1 into context with other known hypoxia-responsive genes, we analyzed the kinetics of Vegf expression in the same samples. Similarly to Stc-1, Vegf showed a biphasic response with an immediate early peak followed by a delayed late response (Fig. 1B). Furthermore, in situ hybridization localized the Stc-1 expression mainly to cardiomyocytes (Fig. 1, C and D).


Figure 1
View larger version (76K):
[in this window]
[in a new window]

  		Fig. 1. Hypoxia induces stanniocalcin-1 (STC-1) in vivo. Shown in quantitative analysis of Stc-1 (A) and Vegf (B) mRNA in hearts of wild-type (WT) mice (n = 4–6/group) exposed to hypoxia. Heart tissue was harvested at indicated time points. Values were normalized against beta-2-microglobulin (beta2m) mRNA levels and represent means ± SD. In situ hybridization of Stc-1 was performed in hypoxic hearts with antisense (C) and sense (D) probes. Scale bar = 100 µm.

 
Reduced primary and lack of secondary Stc-1 induction by HOPC in Il-6–/– mice. Dawn et al. (7) reported that IL-6 is a mediator of the late-IP effect observed in myocardium. To investigate the role of IL-6 for the in vivo upregulation of Stc-1 in the heart after HOPC, we exposed Il-6–/– mice to 8% oxygen for 6 h. The expression of Stc-1 mRNA was quantified at the time points that gave maximum responses in WT mice (during hypoxia and 48 h after reoxygenation) (Fig. 2A). HOPC induced an early Stc-1 response in the hearts of Il-6–/– mice. The Stc-1 expression, however, remained at a lower level than that observed in the hearts of WT mice, indicating a partial requirement for IL-6 signaling in the primary induction of Stc-1. A similarly altered response of Vegf to HOPC was observed in Il-6–/– mice (Fig. 2B). The second peak of Stc-1 induction at 48 h was absent, as was the Vegf response, in the hearts of the Il-6–/– mice, indicating the requirement for IL-6 in the late phase of Stc-1 induction by HOPC.


Figure 2
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 2. Reduced Stc-1 induction in Il-6–/– mice. Shown is quantitative analysis of Stc-1 (A) and Vegf (B) mRNA in hearts of Il-6–/– mice (n = 4/group) exposed to hypoxia. Heart tissue was harvested at indicated time points. Values were normalized against beta2m mRNA levels and represent means ± SD.

 
Oxygen deprivation induces Stc-1 in cardiac myocytes in vitro. To investigate whether expression of Stc-1 is directly regulated by hypoxia in myocardial cells, we cultured the cardiomyocyte cell line HL-1 in a 99.5% nitrogen atmosphere for 6 h, after which the cells were returned to normal culture conditions. We observed an increased Stc-1 expression within 6 h, followed by a return to control levels at 17 h (Fig. 3A). The kinetics of the Stc-1 response followed the pattern of Vegf expression, another classical hypoxia responsive gene (Fig. 3B). The Stc-1 and Vegf responses followed identical time courses, suggesting similar mechanisms of regulation. Immunohistochemical staining of HL-1 cells with rabbit antibodies to STC-1 showed that hypoxia induced an increased cytoplasmic accumulation of STC-1 protein with a granular distribution (Fig. 3, C and D).


Figure 3
View larger version (67K):
[in this window]
[in a new window]

  		Fig. 3. Hypoxia induces Stc-1 in HL-1 cells. Shown is quantitative analysis of mRNA levels of Stc-1 (A) and Vegf (B) in HL-1 cells cultured for 6 h in 99.5% nitrogen and returned to normal culture conditions for indicated times. Untreated cells served as controls. Values are normalized against beta2m mRNA levels and represent means ± SD. STC-1 immunohistochemistry is shown of control HL-1 cells (C) and HL-1 cells after 6 h of hypoxia (D). Scale bar = 20 µm.

 
IL-6 induces elevated Stc-1 expression in HL-1 cardiomyocytes. Treatment of HL-1 cells with IL-6 (5 ng/ml) induced increased Stc-1 expression with a maximum at 6 h and a gradual decline during the following 48 h (Fig. 4).


Figure 4
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 4. IL-6 induces Stc-1 in HL-1 cells. HL-1 cells were cultured in the presence of 5 ng/ml IL-6, and mRNA levels of Stc-1 were quantified at indicated time points. Untreated cells served as controls. Values are normalized against beta2m mRNA levels and represent means ± SD.

 
Mitochondrial localization of STC-1. To further characterize the subcellular localization of STC-1, we transfected HL-1 cells with STC-1 cDNA containing a carboxy-terminal FLAG sequence. Costaining of the transfected cells with a monoclonal antibody to FLAG and with MitoTracker revealed a codistribution, demonstrating mitochondrial targeting of expressed Stc-1 (Fig. 5).


Figure 5
View larger version (39K):
[in this window]
[in a new window]

  		Fig. 5. Mitochondrial localization of STC-1. HL-1 cells transiently transfected with STC-1-FLAG cDNA were stained with monoclonal antibodies to FLAG (A) and with MitoTracker (B). The merged picture (C) shows the targeting of STC-1 to mitochondria. Scale bar = 20 µm.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We present here findings demonstrating that HOPC induces elevated expression of Stc-1 in the heart with IL-6 as a key signaling molecule. The initial Stc-1 response that occurs within a few hours of hypoxic stress appears to be partially dependent on IL-6 signaling, since a Stc-1 response of lower magnitude but with similar timing as in WT mice was observed in the hearts of Il-6–/– mice. Exposure of HL-1 cells to hypoxia in vitro also induced a rapid Stc-1 response without measurable induction of IL-6 (data not shown). This indicates that other signaling pathways contribute to the induction of rapid Stc-1 responses during hypoxia. Yeung et al. (35) reported evidence for a hypoxia-inducible factor-dependent increase in Stc-1 expression in nasopharyngeal cancer cells. Hence, it is tempting to suggest that hypoxia-inducible factor-dependent pathways may contribute to the early Stc-1 response to hypoxia in cardiomyocytes as well. The later Stc-1 response to HOPC occurred 24–48 h posthypoxia. This later peak of Stc-1 response was nevertheless absent from the hearts of Il-6–/– mice exposed to HOPC and therefore appears to depend on IL-6 signaling. Chandrasekar et al. (2) subjected cultures of rat cardiomyocytes to 15 min of ischemia followed by reperfusion. They reported an upregulated expression of both IL-6 and IL-6 receptor within 1 h of reperfusion, and the levels remained elevated for up to 6 h. This time course coincides with the first window of protection associated with preconditioning. In addition, Roy et al. (22) showed that 30 min of ischemia followed by reperfusion of rat myocardial cells induced elevated IL-6 gene expression on days 2 and 3 after reperfusion. This coincides with the second window of protection following HOPC. These results are in agreement with our findings, indicating a key role of IL-6 for both windows of protection by HOPC.

Hypoxic stress induces IL-6 expression also in extracardiac organs and tissues, i.e., in lung and kidney (33, 34). One might speculate that the contribution of IL-6 to the early Stc-1 response occurs in an auto- or paracrine manner, whereas circulating IL-6 induces the later response. However, the relative contributions of the different sources of IL-6 to the induction of Stc-1 expression after HOPC need to be established.

Given the high degree of evolutionary conservation of STC-1, it is conceivable that it mediates similar functions in both fish and mammalians, i.e., protection against toxic hypercalcemia. We showed that overexpression of STC-1 in human neural cells increased their resistance to treatment with thapsigargin, which mobilizes intracellular calcium stores (37). Sheikh-Hamad et al. (25) reported that treatment of cultured rat cardiomyocytes with STC-1 slowed their beating rate. Moreover, they showed that the addition of STC-1 lowered the rise in intracellular calcium and presented evidence that STC-1 acts as a reversible blocker of transmembrane calcium currents through L-type channels. Smart et al. (27) recently reported that pretreatment of neonatal rat cardiomyocytes with IL-6 caused a significant decrease in the amplitude of their Ca2+ oscillations. In light of our present findings, this effect might be mediated through IL-6-induced STC-1 expression.

Because mammalian STC-1, in contrast to the fish protein, does not occur in significant amounts in the circulation, it is suggested to act locally in an autocrine or paracrine fashion. McCudden et al. (15) first reported binding of STC-1 to the inner membrane of mitochondria. They also presented evidence that treatment with recombinant STC-1 protein induced enhanced electron transport in submitochondrial particles. We have previously reported that a high expression of STC-1 confers increased resistance of the mitochondrial membrane potential to bacterial toxins, mediating potassium ionophore effects (29). Here, we also demonstrate that most of the ectopic expression of STC-1 in HL-1 cells is targeted to mitochondria. Smart et al. (27) observed that pretreatment of cultured rat cardiomyocytes with IL-6 induced functional resistance to hypoxic stress of the mitochondria. Given that IL-6 strongly induces STC-1 expression, this is of particular interest since Ellard et al. (9) very recently reported that treatment of mitochondria with recombinant STC-1 protein induces mild uncoupling. Altered mitochondrial metabolism, and in particular uncoupling, has been implicated as a central functional mechanism behind ischemia-induced cardioprotection (for recent reviews, see Refs. 5, 23). Furthermore, the recent article by Koizumi et al. (11) shows that STC-1 prevents oubain-induced cell hypercontracture in cardiomyocytes. Hypercontracture is responsible for a large part of the damage in the heart after reperfusion (18, 19, 26). An increased level of STC-1 could potentially decrease this damage.

In summary, the induction of cardiac STC-1 expression by HOPC described here represents a novel molecular pathway that may be exploited for the prevention and management of ischemic heart damage.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
These studies were supported by The Academy of Finland, The Sigrid Jusélius Foundation, The Magnus Ehrnrooth Foundation, The Queen Victoria and King Gustaf V Foundation, Finska Läkaresällskapet, and Biocentrum Helsinki.


   ACKNOWLEDGMENTS
 
We thank Tiiu Arumäe and Anna Wilenius for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. C. Andersson, Dept. of Pathology, Haartman Institute, Univ. of Helsinki, PO Box 21 (Haartmaninkatu 3), FI-00014 Helsinki, Finland (e-mail: leif.andersson{at}helsinki.fi)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* J. A. Westberg and M. Serlachius contributed equally to this work. Back


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 22: 393–403, 2002.[Web of Science][Medline]
  2. Chandrasekar B, Mitchell DH, Colston JT, Freeman GL. Regulation of CCAAT/enhancer binding protein, interleukin-6, interleukin-6 receptor, and gp130 expression during myocardial ischemia/reperfusion. Circulation 99: 427–433, 1999.[Abstract/Free Full Text]
  3. Chang AC, Dunham MA, Jeffrey KJ, Reddel RR. Molecular cloning and characterization of mouse stanniocalcin cDNA. Mol Cell Endocrinol 124: 185–187, 1996.[CrossRef][Web of Science][Medline]
  4. Chang AC, Janosi J, Hulsbeek M, de Jong D, Jeffrey KJ, Noble JR, Reddel RR. A novel human cDNA highly homologous to the fish hormone stanniocalcin. Mol Cell Endocrinol 112: 241–247, 1995.[CrossRef][Web of Science][Medline]
  5. Chen Q, Camara A, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol 292: C137–C147, 2007.[Abstract/Free Full Text]
  6. Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci USA 95: 2979–2984, 1998.[Abstract/Free Full Text]
  7. Dawn B, Xuan YT, Guo Y, Rezazadeh A, Stein AB, Hunt G, Wu WJ, Tan W, Bolli R. IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovasc Res 64: 61–71, 2004.[Abstract/Free Full Text]
  8. Eisen A, Fisman EZ, Rubenfire M, Freimark D, McKechnie R, Tenenbaum A, Motro M, Adler Y. Ischemic preconditioning: nearly two decades of research. A comprehensive review. Atherosclerosis 172: 201–210, 2004.[CrossRef][Web of Science][Medline]
  9. Ellard JP, McCudden CR, Tanega C, James KA, Ratkovic S, Staples JF, Wagner GF. The respiratory effects of stanniocalcin-1 (STC-1) on intact mitochondria and cells: STC-1 uncouples oxidative phosphorylation and its actions are modulated by nucleotide triphosphates. Mol Cell Endocrinol 264: 90–101, 2007.[CrossRef][Web of Science][Medline]
  10. Keira SM, Ferreira LM, Gragnani A, da Silva Duarte I, Bittencourt Campaner A, de Souza Durão M Jr. Experimental model for establishment of hypoxia in 75 cm2 culture flasks. Acta Cir Bras 19: 23–27, 2004.
  11. Koizumi K, Hoshiai M, Ishida H, Ohyama K, Sugiyama H, Naito A, Toda T, Nakazawa H, Nakazawa S. Stanniocalcin 1 prevents cytosolic Ca2+ overload and cell hypercontracture in cardiomyocytes. Circ J 71: 796–801, 2007.[CrossRef][Web of Science][Medline]
  12. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72: 1293–1299, 1993.[Abstract/Free Full Text]
  13. Lasley RD, Anderson GM, Mentzer RM Jr. Ischaemic and hypoxic preconditioning enhance postischaemic recovery of function in the rat heart. Cardiovasc Res 27: 565–570, 1993.[Abstract/Free Full Text]
  14. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 h after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88: 1264–1272, 1993.[Abstract/Free Full Text]
  15. McCudden CR, James KA, Hasilo C, Wagner GF. Characterization of mammalian stanniocalcin receptors. Mitochondrial targeting of ligand and receptor for regulation of cellular metabolism. J Biol Chem 277: 45249–45258, 2002.[Abstract/Free Full Text]
  16. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136, 1986.[Abstract/Free Full Text]
  17. Olsen HS, Cepeda MA, Zhang QQ, Rosen CA, Vozzolo BL. Human stanniocalcin: a possible hormonal regulator of mineral metabolism. Proc Natl Acad Sci USA 93: 1792–1796, 1996.[Abstract/Free Full Text]
  18. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 38: 291–300, 1998.[Free Full Text]
  19. Piper HM, Meuter K, Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg 75: S644–S648, 2003.[Abstract/Free Full Text]
  20. Ran R, Xu H, Lu A, Bernaudin M, Sharp FR. Hypoxia preconditioning in the brain. Dev Neurosci 27: 87–92, 2005.[CrossRef][Web of Science][Medline]
  21. Rowland RT, Meng X, Cleveland JC, Meldrum DR, Harken AH, Brown JM. Cardioadaptation induced by cyclic ischemic preconditioning is mediated by translational regulation of de novo protein synthesis. J Surg Res 71: 155–160, 1997.[CrossRef][Web of Science][Medline]
  22. Roy S, Khanna S, Kuhn DE, Rink C, Williams WT, Zweier JL, Sen CK. Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix. Physiol Genomics 25: 364–374, 2006.[Abstract/Free Full Text]
  23. Sack MN. Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res 72: 210–219, 2006.[Abstract/Free Full Text]
  24. Serlachius M, Zhang KZ, Andersson LC. Stanniocalcin in terminally differentiated mammalian cells. Peptides 25: 1657–1662, 2004.[CrossRef][Web of Science][Medline]
  25. Sheikh-Hamad D, Bick R, Wu GY, Christensen BM, Razeghi P, Poindexter B, Taegtmeyer H, Wamsley A, Padda R, Entman M, Nielsen S, Youker K. Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure. Am J Physiol Heart Circ Physiol 285: H442–H448, 2003.[Abstract/Free Full Text]
  26. Siegmund B, Schluter KD, Piper HM. Calcium and the oxygen paradox. Cardiovasc Res 27: 1778–1783, 1993.[Free Full Text]
  27. Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ. IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes. Cardiovasc Res 69: 164–177, 2006.[Abstract/Free Full Text]
  28. Tang Y, Pacary E, Freret T, Divoux D, Petit E, Schumann-Bard P, Bernaudin M. Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke. Neurobiol Dis 21: 18–28, 2006.[CrossRef][Web of Science][Medline]
  29. Teplova V, Jaaskelainen E, Salkinoja-Salonen M, Saris NE, Serlachius M, Li FY, Andersson LC. Differentiated Paju cells have increased resistance to toxic effects of potassium ionophores. Acta Biochim Pol 51: 539–544, 2004.[Web of Science][Medline]
  30. Wagner GF, Hampong M, Park CM, Copp DH. Purification, characterization, and bioassay of teleocalcin, a glycoprotein from salmon corpuscles of Stannius. Gen Comp Endocrinol 63: 481–491, 1986.[CrossRef][Web of Science][Medline]
  31. Westberg JA, Serlachius M, Lankila P, Penkowa M, Hidalgo J, Andersson LC. Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling. Stroke 38: 1025–1030, 2007.[Abstract/Free Full Text]
  32. Yamauchi-Takihara K, Ihara Y, Ogata A, Yoshizaki K, Azuma J, Kishimoto T. Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 91: 1520–1524, 1995.[Abstract/Free Full Text]
  33. Yan SF, Tritto I, Pinsky D, Liao H, Huang J, Fuller G, Brett J, May L, Stern D. Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem 270: 11463–11471, 1995.[Abstract/Free Full Text]
  34. Yan SF, Zou YS, Mendelsohn M, Gao Y, Naka Y, Du Yan S, Pinsky D, Stern D. Nuclear factor interleukin 6 motifs mediate tissue-specific gene transcription in hypoxia. J Biol Chem 272: 4287–4294, 1997.[Abstract/Free Full Text]
  35. Yeung HY, Lai KP, Chan HY, Mak NK, Wagner GF, Wong CK. Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells. Endocrinology 146: 4951–4960, 2005.[Abstract/Free Full Text]
  36. Yoshiko Y, Aubin JE. Stanniocalcin 1 as a pleiotropic factor in mammals. Peptides 25: 1663–1669, 2004.[CrossRef][Web of Science][Medline]
  37. Zhang K, Lindsberg PJ, Tatlisumak T, Kaste M, Olsen HS, Andersson LC. Stanniocalcin: a molecular guard of neurons during cerebral ischemia. Proc Natl Acad Sci USA 97: 3637–3642, 2000.[Abstract/Free Full Text]
  38. Zhang SX, Miller JJ, Gozal D, Wang Y. Whole-body hypoxic preconditioning protects mice against acute hypoxia by improving lung function. J Appl Physiol 96: 392–397, 2004.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/H1766    most recent
00017.2007v1
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 Web of Science
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 Google Scholar
Google Scholar
Right arrow Articles by Westberg, J. A.
Right arrow Articles by Andersson, L. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Westberg, J. A.
Right arrow Articles by Andersson, L. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.