| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B
degradation
1 Angiogenesis Research Center, 2 Division of Molecular Medicine, Beth Israel Deaconess Medical Center, 3 Angiogenesis Research Center, Dartmouth Medical School, Hanover, New Hampshire 03756
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
PR-39 inhibits proteasome-mediated I
B
degradation
and might protect against ischemia-reperfusion injury. We
studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which
lacks the ability to prevent IB degradation, in a rat heart
ischemia-reperfusion model. After 30 min of
ischemia and 24 h of reperfusion, cardiac function,
infarct size, neutrophil infiltration, and myeloperoxidase activity
were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11
at the time of reperfusion reduced infarct size by 65% and 57%,
respectively, which improved blood pressure, left ventricular systolic
pressure, and relaxation and contractility (±dP/dt)
compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of IB degradation and subsequent
inhibition of nuclear factor-B-dependent adhesion molecules. The
active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.
rat; reactive oxygen species
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
DESPITE ADVANCES in
the management of acute myocardial ischemia, limitation of
ischemia-reperfusion injury remains an important clinical
challenge. Recently, we demonstrated that a naturally occurring
proline-arginine-rich PR-39 peptide selectively inhibits proteasome-mediated degradation of IB, resulting in inactivation of transcription nuclear factor (NF)B (7). Studies of
acute myocardial infarction and acute pancreatitis models in mice
demonstrated that systemic administration of the peptide reduced
expression of leukocyte adhesion molecules, including intercellular
adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), as well as generally suppressed NFB-dependent transcription
(7). Activation of NFB due to degradation of its
cytoplasmic IB inhibitor is an early event in myocardial
ischemia-reperfusion injury (4, 17). This increase
in NFB-dependent transcription results in enhanced expression of
endothelial adhesion molecules, including P-selectin (13),
ICAM-1 (11), and VCAM-1 (27), and thus
initiates rolling and transmigration of circulating neutrophils and
monocytes (14). We hypothesized that locally administered PR-39 might protect against myocardial ischemia-reperfusion
injury by suppressing NFB-dependent expression of these adhesion
molecules, thereby inhibiting accumulation and/or activation of
invading white blood cells and reducing local inflammatory response.
To study the mechanism for PR-39 protection against
ischemia-reperfusion injury, we investigated the effect of
PR-39 and two derivatives: PR-11 and PR-11AAA. PR-11 comprises the
first 11 amino acids of the PR-39 sequence, and in PR-11AAA the first
three arginines are replaced by alanines, which block its inhibitory effect on tumor necrosis factor- (TNF-)-induced degradation of
IB in vitro. We find that intramyocardial injection of PR-39 and
PR-11 into the area of myocardium at risk 30 min after occlusion of the
proximal coronary artery and before restoration of blood flow inhibits
ischemia-induced upregulation of ICAM-1 and VCAM-1 and
decreases accumulation of neutrophils, resulting in reduction in the
infarct size and enhanced preservation of myocardial function. At the
same time, injections of PR-11AAA peptide had no effect on any of these
end points. The data support the hypothesis that ischemia-induced activation of NFB-dependent expression of
endothelial adhesion molecules results in accumulation of neutrophils
and subsequent ischemia-reperfusion injury. PR39 and PR-11
peptides are able to disrupt this cycle by preventing degradation of
IB by the proteasome pathway.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Animal model. Male Sprague-Dawley rats (250-300 g) were anesthetized with ketamine 100 mg/kg and xylazine 10 mg/kg, intubated, and ventilated (Tidal volume: 2 ml, 55 min, model 683, Harvard Apparatus; Holliston, MA). An electrocardiogram (ECG) was recorded during ischemia-reperfusion and during the final study using needle electrodes. At the final study, the carotid artery was cannulated to record blood pressure and left ventricular pressure (LVP) using dedicated physiological monitors (model 200, Micro-Med; Louisville, KY) interfaced with a computer.
For ischemia-reperfusion, a left fifth intercostal thoracotomy was performed under sterile conditions. The pericardium was incised, and the left anterior descending coronary artery (LAD) was ligated for 30 min. At the start of reperfusion the animals were randomized to receive intramyocardial injections of PR-39, PR-11, PR-11AAA (250 µM, 40 µl/kg), or vehicle (phosphate-buffered saline, pH = 7.4) into the ischemic part of the heart in two equal injections. The chest was closed, and ECG and blood pressure were recorded for another 15 min. Successful ligation and reperfusion of the LAD were confirmed by ECG changes and discoloring of the subtended myocardium. After 24 h, the animal was reanesthetized and ventilated as before. The carotid artery was cannulated for aortic blood pressure and LVP recording. Subsequently, the LAD was religated at the previous level, and 0.3 ml 4% Evans blue was injected into the aorta 5 min before euthanasia. After harvest, the heart was processed for macroscopic, biochemical, and histologic analysis. The study was compliant with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985) and was approved by the institutional Animal Care and Use Committee.Analysis of physiological data.
BP, ECG, LVP, contractility (+dP/dt) and relaxivity
(
dP/dt), and the relaxation constant tau were recorded at
500 Hz and analyzed by the Digi-med system integrator model 200. Before
ligation and at the final study, stable recordings of 10-15 min
were obtained and physiological parameters were averaged over 5 min.
Stable recordings were obtained during the last 10 min of
ischemia and the last 5 min of reperfusion, and parameters were
averaged over 2-5 min.
Area at risk and infarct areas calculation. The excised heart was rinsed with phosphate-buffered saline three times and cut in five cross sections (1 mm). Cross sections were incubated in 1% 2,3,5-triphenyltetrazolium chloride (Sigma; St. Louis, MO) for 25 min at 25°C. Digital photographs of the cross sections were made, and the area at risk, the vital area, and the infarcted area were delineated by an observer blinded to treatment using computer-assisted image analysis (Optimas 6.0).
Measurement of tissue myeloperoxidase activity and Western blot
analysis.
A cross section 2 mm apical from the ligature was divided into a
nonischemic area and ischemic area (300-µg samples),
snap frozen in liquid nitrogen, and stored at 80°C. Myocardial
myeloperoxidase (MPO) activity was measured according to the method
described by Mullane et al. (20). In brief, the frozen
myocardial tissue was pulverized, weighed, and suspended in 1 ml of 50 mM potassium phosphate buffer solution (pH 6.0) containing 0.5%
(wt/vol) hexadecyltrimethylammonium bromide (Sigma). The samples were
then blended for 90 s (30 s, 3×), sonicated for 10 s,
freeze-thawed three times with liquid nitrogen, and again sonicated for
10 s. Specimens were ultracentrifuged at 45,000 g for
15 min, and the volume of supernatant was measured. The supernatant (10 ml) was mixed with 290 µl of 50 mM potassium phosphate buffer
solution (pH 6.0) containing 0.167 mg/ml o-dianisidine hydrochloride (Sigma) and 0.0005% (vol/vol) hydrogen peroxide. The
change in absorbance at 460 nm was measured every 30 s for 4 min
using a microplate reader. One unit of MPO activity was defined as the
amount needed to degrade 1 mmol peroxide/min at 25°C, and the result
was expressed as units of MPO per microgram of protein.
B antibody (Santa Cruz; Santa Cruz, CA) for 1 h at room
temperature. After being washed with phosphate-buffered saline, the
membrane was incubated with IgG horseradish peroxidase (1:2,000) for
1 h. The membrane was again washed three times with phosphate-buffered saline and then developed using the ECL kit (Amersham), followed by exposure to Kodak XAR film. Equal loading of
various samples was confirmed by Ponceau staining.
Histologic analysis. A cross section 3 mm apical from the ligature was fixed with 10% formaldehyde overnight, embedded in paraffin, sectioned into 5-µm sections, and stained with hematoxylin and eosin. From each section, five and two high power fields (HPF, 400×) were randomly selected from the area at risk and nonischemic area, respectively. In each HPF, polymorphonuclear neutrophils (PMNs) were counted by an experienced observer blinded to treatment assigned. The results were summated for final neutrophil counts.
PR-39 and PR-11. PR-39 and PR-11 peptides were synthesized by CS Bio (San Carlos, CA) and dissolved in sterile saline at a concentration of 250 µM. PR-11 is a carboxyl-end truncated form of PR-39 with 11 amino terminus amino acids remaining: Arg-Arg-Arg-Pro-Arg-Pro-Pro-Tyr-Leu-Pro-Arg. In PR-11AAA the first three arginines were replaced by alanines.
IB Westerns.
IB Westerns were performed as previously described (7).
In brief, human umbilical vein endothelial cells (HUVEC) were exposed
to TNF- (5 ng/ml for 10 min) after 45 min of preincubation with
PR-39, PR-11, PR-11AAA (all 500 nM), or the proteasome inhibitor MG132
(10 µM). Cells were lysed, and IB levels were determined by
Western blotting with a rabbit polyclonal antibody.
Measurement of reactive oxygen species. For detection of intracellular reactive oxygen species (ROS) level, human coronary adult endothelial cells at 80-90% confluence were serum starved overnight in EBM-2 (Clonetics) medium containing 0.5% serum in a 10-cm plate, were washed twice with prewarmed Hank's balanced salt solution (HBSS; GIBCO BRL), preincubated for 2 h with the PR peptides or known inhibitors, and then incubated in 5 ml HBSS containing 15 µM 2',7'-dichlorofluorescein diacetate (DCFH-DA; Molecular Probes) at 37°C for 30 min. For stimulated ROS measurement, the cells were incubated with phorbol myristate acetate (PMA) or N-phenylmethazonium methosulfate (PMS) for 1 h after 2 h of pretreatment with PR-39. Cells were washed with ice-cold HBSS, gently scraped from the plate, and resuspended in 1 ml of HBSS. DCF fluorescence was measured by fluorescence-assisted cell sorting (FACS, excitation wavelength = 485 nm, emission wavelength = 530 nm) by counting 20,000 viable cells (events) from each sample. Propidium iodide (5 µg/ml) was added to exclude dead cells. Each experiment was done in triplicate and repeated at least two times.
Matrigel pellet assay. Twenty C57/BL6 male mice weighing 20 g were anesthetized with 100 mg/kg ketamine ip. Regular Matrigel (Becton Dickinson; Bedford, MA) was mixed with 5 µg/ml PR-39 on ice. With the use of a 24-gauge needle, 0.5 ml of supplemented Matrigel was injected subcutaneously in the abdominal midline under sterile conditions. Two weeks later, the pellets were harvested and processed for histology. Thin sections (5 µm) were cut and stained with hematoxylin and eosin. Blood vessels (cell-lined tubes or circles containing red blood cells) were counted in 10 random HPF (×400 magnification) by an observer blinded to treatment, and the results were summated over the 10 HPFs
Statistical analysis. Data throughout the manuscript are expressed as means ± SE. Means of treatment groups are compared by ANOVA with least significant difference corrected post hoc analysis of group differences using StatView 5.0.1 (SAS Institute; Cary, NC). P values < 0.05 were considered statistically significant.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
PR-39 and PR-11, but not PR-11AAA,
inhibit IB degradation in endothelial cells.
To test the effect of PR-39, PR-11, and PR-11AAA on proteasome-mediated
degradation of IB, we assessed intracellular IB levels in
HUVEC 45 min after exposure to TNF-. Western blotting demonstrated
complete disappearance of IB in control cells (Fig. 1). At the same stimulus, pretreatment
with either PR-39 or PR-11 (500 nM), but not with PR-11AAA, inhibited
TNF--induced IB degradation by 50 or 25%, respectively,
compared with a general proteasome inhibitor MG132 at high
concentration (10 µM).
|
Rat myocardial ischemia-reperfusion model: acute effects of PR peptides injection. Ischemia was induced by ligation of the LAD in 36 rats, and reperfusion was successfully established in all animals after 30 min of ischemia. One animal in the vehicle (control) group died of ventricular fibrillation within 1 h of ligation, and three animals (1 from the vehicle group and 2 from the PR-39 group) died overnight after several hours of reperfusion. Sixteen rats (8 treated with vehicle and 8 with PR-39) were sham operated with the placement of a suture around the LAD without tying. Data from 48 animals (8 per group) were analyzed. No acute adverse effects of intramyocardial PR-39, PR-11, or PR-11AAA injections (hypotension, arrhythmias, myocardial rupture) were seen in this study.
Before and during ischemia, mean arterial blood pressure was similar in the four groups (Table 1). Shortly after reperfusion and after the intramyocardial injection of PR-39, PR-11, PR-11AAA, or vehicle, there were also no differences in mean arterial blood pressure and heart rate among the groups.
|
Myocardial area at risk and the left ventricular function.
Area at risk, determined by Evans blue dye injection while the LAD was
reoccluded, was similar in all groups (51.9 ± 3.6% in the
vehicle group, 49.8 ± 2.7% in the PR-39 group, and 44.1 ± 3.2% in the PR-11 group, 53.5 ± 2.9 in PR-11AAA group, ANOVA, P = 0.34). Intramyocardial administration of either
PR-39 or PR-11 resulted in a significant (64% and 57%, respectively,
P < 0.0001 for both) reduction in the infarct size
compared with the vehicle group (Fig. 2),
whereas PR-11AAA treatment was similar to the vehicle (Fig. 2).
|
dP/dt (P < 0.05 and P < 0.01 vs. vehicle, respectively). No
differences in end-diastolic pressure, heart rate, or tau were observed
at this time point (Table 1). In sham-operated rats, arterial pressure
during surgery did not change. PR-39 had no effect on the left
ventricular function on sham-operated rats 24 h after surgery. For
instance, left ventricular systolic pressure was 94.4 ± 3.5 mmHg
in vehicle and 94.6 ± 4.6 mmHg in PR-39-treated animals, and
end-diastolic pressures were 9.1 ± 2.4 mmHg and 9.3 ± 2.3 mmHg, respectively
Myocardial neutrophil infiltration and MPO activity.
To assess the impact of PR peptides on myocardial accumulation of white
blood cells, we quantified the presence of PMNs on histologic
sections of the myocardium after 24 h of reperfusion. In
nonischemic territories of the heart, very small numbers of PMNs were counted, and there were no differences among the treatment groups. In contrast, analysis of the area at risk demonstrated high PMN
counts and significant reduction in PR-39- and PR-11- but not in the
PR-11AAA-treated animals (Fig.
3A).
|
Reduction of ICAM-1, VCAM-1, and
increase in IB.
Western analysis performed on samples from the area at risk 24 h
after reperfusion showed a substantial reduction in ICAM-1 and VCAM-1
expression by PR-39 and PR-11, but not by PR-11AAA (Fig.
4), further supporting a reduction of
NFB-dependent protein expression and linking this pathway with
reduction of neutrophil attraction into the area of reperfusion. Most
likely the reduced NFB effects were due to increased levels IB
levels in the ischemic areas of the hearts that were treated
with PR-39 and PR-11 (Fig. 4)
|
PR peptides do not exhibit anti-p47phox
effect.
A recently published study suggests that PR-39 interacts with the
p47phox component of NADPH oxidase (15,
25) and that this interaction may result in reduced generation
of ROS such as H2O2 and ONOO
that
would in turn contribute to reduction in the
ischemia-reperfusion injury. To evaluate this
potential mechanism, we measured the formation of ROS in human cardiac
adult endothelial cells in the presence of PR-39, PR-11, and a known
inhibitor of NADPH oxidase diphenyleneiodonium (DPI). Neither PR-39 nor
PR-11 inhibited the formation of ROS, whereas DPI (100 µM) reduced it
by 70% (Fig. 5A). PMA and PMS
stimulated ROS production 1.4- and 1.9-fold, respectively, which was
not affected by preincubation with 5 µg/ml PR-39 (Fig.
5B). Because another aspect of PR-39 activity is the inhibition of proteasome-mediated degradation of hypoxia-inducible factor (HIF)-1, we assessed PR-39-induced angiogenesis in
p47phox knockout and heterozygous control mice.
The extent of angiogenesis induced by the peptide was the same in both
settings (Fig. 5C).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The principal findings of this study are that PR-39 peptide and
its derivative PR-11, following local injection into the transiently ischemic region of the left ventricle, protect against
ischemia-reperfusion injury through inhibition of degradation
of IB. This in turn resulted in reduced activation of
NFB-dependent events such as the expression of the adhesion
molecules ICAM-1 and VCAM-1 on endothelial cells in the
ischemic but viable myocardium. This was accompanied by a
reduction in myocardial accumulation of PMN and a decrease in the
severity of reperfusion injury as assessed by the infarct size and left
ventricular function measures. A mutant form of PR11, PR-11AAA, a
peptide that did not prevent TNF--induced IB degradation in
cultured endothelial cells, was not effective in preventing the
expression of NFB-dependent genes VCAM-1 and ICAM-1 in an
ischemia-reperfusion injury model in the rat heart and did
not reduce the size or severity of myocardial injury.
The evidence summarized in this study, including reduction in the
number of infiltrating neutrophils, reduced MPO activity, and reduced
infarct size in the PR-39/PR-11-treated hearts, strongly supports the
concept that ischemia-induced activation of NFB-dependent gene expression and, in particular, expression of adhesion molecules such as ICAM-1 and VCAM-1, underlies ischemia-reperfusion injury.
We propose that the ability of PR-39 and its PR-11 derivative peptides
to block proteasome-mediated degradation of IB is the mechanism
through which these peptides exert their effect in
ischemia-reperfusion injury. The ability of PR-39 to block ischemia-reperfusion injury has recently been demonstrated in several models, including the mesentery (15) and the heart
(10). In the case of mesenteric ischemia,
systemically administered PR-39 in the rat inhibited leukocyte rolling
and adherence in the inflamed mesentery and reduced the extent of
reperfusion injury. Likewise, systemic infusion of PR-39 in a mouse
cardiac ischemia-reperfusion model reduced PMN accumulation,
mitigated ischemia-reperfusion injury, lowered the extent of
myocardial necrosis, and preserved left ventricular function
(10). However, the molecular mechanism of this effect
remained unclear. We have recently shown that PR-39 binds to the
7-subunit of the 20S proteasome, resulting in inhibition of IB
(7) and HIF-1 degradation (18).
Unlike the usual proteasome inhibitor, PR-39 activity appears to be
relatively selective to these two proteins with no significant effect
on overall cellular protein degradation and no activation of the heat
shock response (7).
At the same time, other studies suggested an alternative mechanism of
PR-39 activity. In particular, the presence of proline-rich sequence
suggested the possibility of interactions with SH3 domain-containing proteins, including a transmembrane protein p130(Cas) (3)
and the p47phox subunit of NADPH
(25). Whereas the biological effect of a potential PR39-p130(Cas) interaction still remains unclear, it is highly unlikely
that inhibition of NADPH activity mediates any of PR-39 biological
activities. Several lines of evidence from this study support this
conclusion. Although both PR-11 and PR-11AAA peptides in this study
have the same putative SH3 domain-binding sequence, only PR-11
inhibited TNF--induced IB degradation and VCAM/ICAM expression
in vivo. Furthermore, neither PR-39 nor PR-11 blocked baseline or
PMA/PMS-induced generation of ROS in cultured endothelial cells.
Finally, PR-39 was able to induce angiogenesis in Matrigel pellets
implanted in p47phox/ mice, a
process that depends on inactivation of proteasome-mediated HIF-1
degradation (7). Moreover, a recent study of
ischemia-reperfusion in
p47phox/ mice demonstrated that
the extent of reperfusion injury was comparable to heterozygote
littermate control mice (9).
Whereas many factors could have contributed to the difference between this observation and the original reports of PR-39-mediated inhibition of NADPH activity (1, 15), including differences in species and cell types, the most likely explanation is in the amount of peptide used. The PR-39 concentration reportedly required for the anti-NADPH effect, 5 µM (15), is significantly higher than the dose employed in the study of Gao et al. (7) or in the present study (estimated tissue concentration of 250 nM, based on a 10% retention of PR-39 during the first hour, and a local distribution volume that is 100-fold larger than the injection volume as estimated from immunohistochemistry). In vitro, as little as 100 nM of PR-39 is sufficient to fully inhibit 20S proteasome activity (Y. Gao and M. Simons, unpublished observations). Thus it is highly unlikely that the inhibition of NADPH oxidase at physiological and therapeutic concentrations of PR-39 is relevant for mitigation of ischemia-reperfusion injury. Finally, it is unlikely that the documented angiogenic effect of PR-39 (18) has contributed to the reduction in infarct size in this model of acute ischemia-reperfusion given the short duration of reperfusion (24 h).
Evidence from other studies supports the concept that the inhibition of
endothelial adhesion molecules or their CD11/CD18 leukocyte receptors
protects against ischemia-reperfusion injury. Thus both the
infarct size and the extent of neutrophil invasion after
ischemia-reperfusion injury in ICAM-1- and CD18-deficient mice
are reduced by more than 50% (19, 21). Infusion of a monoclonal antibody against ICAM-1 reduced myocardial infarct size in
dog (8), rabbit (28), and rat (12,
26) models of ischemia-reperfusion injury. Likewise,
neutralizing antibodies against the 4-integrin (VLA4, CD49d), the
receptor for VCAM-1, reduced cerebral infarcts in rats after transient
ischemia (23). In addition to ICAM-1 and VCAM-1,
E-selectin (24) and P-selectin (16) are
considered important cytokine-induced and NFB-mediated adhesion
molecules in inflammatory processes such as
ischemia-reperfusion injury (22). A novel
synthetic proteasome inhibitor PS-519 reduced ischemia-reperfusion injury in the rat Langendorff preparation, which was associated with attenuation of P-selectin expression in the
coronary microvasculature (2).
Thus there is firm experimental support for the concept that inhibition
of NFB-dependent gene expression by either gene disruption or
inactivation of expressed proteins would result in amelioration of
ischemic injury. PR-39 should be especially effective in this regard given its unique ability to selectively inhibit
proteasome-mediated IB degradation thereby inhibiting expression
of relevant NFB-dependent genes.
Recent clinical trials with antibodies against single adhesion
molecules, including CD18 and CD11b administered in a systemic fashion,
have produced disappointing results (5, 6). In contrast to
this approach, we investigated local injections into the area at risk
of peptides capable of suppressing the activation of all
NFB-dependent genes, including endothelial cell adhesion molecules.
In our view, this strategy has great clinical potential, but this is
clearly an area that requires further study in patients with coronary
heart disease.
In conclusion, PR39 is an effective inhibitor of
ischemia-reperfusion injury in the rat heart in vivo. The
peptide limits the infarct size and prevents cardiac dysfunction after
temporary coronary ligation by reducing influx of neutrophils. Its
effect is most likely based on inhibition of the 20S
proteasome-mediated degradation of IB and subsequent inhibition
of NFB-dependent expression of adhesion molecules. The active
sequence is located in the first 11 amino acids, suggesting a potential
for oligopeptide therapy as an adjunct to revascularization.
| |
ACKNOWLEDGEMENTS |
|---|
This study was supported through National Heart, Lung, and Blood Institute Grants HL-53793 and HL636-09, EIA Award 9940074 of the American Heart Association and by MicroHeart, Inc. M. Simons is an Established Investigator of the AAHA.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: M. J. Post, Angiogenesis Research Center, Dartmouth Hitchcock Medical Center HB 7700, 1 Medical Center Dr., Lebanon, NH 03756 (E-mail: Mark.J.Post{at}Hitchcock.org).
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.
Received 31 January 2001; accepted in final form 24 August 2001.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Al-Mehdi, AB,
Zhao G,
Dodia C,
Tozawa K,
Costa K,
Muzykantov V,
Ross C,
Blecha F,
Dinauer M,
and
Fisher AB.
Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+.
Circ Res
83:
730-737,
1998
2.
Campbell, B,
Adams J,
Shin YK,
and
Lefer AM.
Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart.
J Mol Cell Cardiol
31:
467-476,
1999[Web of Science][Medline].
3.
Chan, YR,
and
Gallo RL.
PR-39, a syndecan-inducing antimicrobial peptide, binds and affects p130(Cas).
J Biol Chem
273:
28978-28985,
1998
4.
Chandrasekar, B,
and
Freeman GL.
Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium.
FEBS Lett
401:
30-34,
1997[Web of Science][Medline].
5.
DeGraba, TJ.
The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy.
Neurology
51:
S62-S68,
1998
6.
Dove, A.
CD18 trials disappoint again.
Nat Biotechnol
18:
817-818,
2000[Web of Science][Medline].
7.
Gao, Y,
Lecker S,
Post MJ,
Hietaranta AJ,
Li J,
Volk R,
Li M,
Sato K,
Saluja AK,
Steer ML,
Goldberg AL,
and
Simons M.
Inhibition of ubiquitin-proteasome pathway-mediated IkappaBalpha degradation by a naturally occurring antibacterial peptide.
J Clin Invest
106:
439-448,
2000[Web of Science][Medline].
8.
Hartman, JC,
Anderson DC,
Wiltse AL,
Lane CL,
Rosenbloom CL,
Manning AM,
Humphrey WR,
Wall TM,
and
Shebuski RJ.
Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1.
Cardiovasc Res
30:
47-54,
1995[Web of Science][Medline].
9.
Hoffmeyer, MR,
Jones SP,
Ross CR,
Sharp B,
Grisham MB,
Laroux FS,
Stalker TJ,
Scalia R,
and
Lefer DJ.
Myocardial Ischemia/Reperfusion injury in NADPH oxidase-deficient mice.
Circ Res
87:
812-817,
2000
10.
Hoffmeyer, MR,
Scalia R,
Ross CR,
Jones SP,
and
Lefer DJ.
PR-39, a potent neutrophil inhibitor, attenuates myocardial ischemia-reperfusion injury in mice.
Am J Physiol Heart Circ Physiol
279:
H2824-H2828,
2000
11.
Howard, EF,
Chen Q,
Cheng C,
Carroll JE,
and
Hess D.
NF-kappa B is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells.
Neurosci Lett
248:
199-203,
1998[Web of Science][Medline].
12.
Ioculano, M,
Squadrito F,
Altavilla D,
Canale P,
Squadrito G,
Campo GM,
Saitta A,
and
Caputi AP.
Antibodies against intercellular adhesion molecule 1 protect against myocardial ischaemia-reperfusion injury in rat.
Eur J Pharmacol
264:
143-149,
1994[Web of Science][Medline].
13.
Jones, SP,
Girod WG,
Palazzo AJ,
Granger DN,
Grisham MB,
Jourd'Heuil D,
Huang PL,
and
Lefer DJ.
Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase.
Am J Physiol Heart Circ Physiol
276:
H1567-H1573,
1999
14.
Jordan, JE,
Zhao ZQ,
and
Vinten-Johansen J.
The role of neutrophils in myocardial ischemia-reperfusion injury.
Cardiovasc Res
43:
860-878,
1999
15.
Korthuis, RJ,
Gute DC,
Blecha F,
and
Ross CR.
PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction.
Am J Physiol Heart Circ Physiol
277:
H1007-H1013,
1999
16.
Lefer, DJ.
Pharmacology of selectin inhibitors in ischemia/ reperfusion states.
Annu Rev Pharmacol Toxicol
40:
283-294,
2000[Web of Science][Medline].
17.
Li, C,
Browder W,
and
Kao RL.
Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart.
Am J Physiol Heart Circ Physiol
276:
H543-H552,
1999
18.
Li, J,
Post M,
Volk R,
Gao Y,
Li M,
Metais C,
Sato K,
Tsai J,
Aird W,
Rosenberg RD,
Hampton TG,
Sellke F,
Carmeliet P,
and
Simons M.
PR39, a peptide regulator of angiogenesis.
Nat Med
6:
49-55,
2000[Web of Science][Medline].
19.
Metzler, B,
Mair J,
Lercher A,
Schaber C,
Hintringer F,
Pachinger O,
and
Xu Q.
Mouse model of myocardial remodelling after ischemia: role of intercellular adhesion molecule-1.
Cardiovasc Res
49:
399-407,
2001
20.
Mullane, KM,
Kraemer R,
and
Smith B.
Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium.
J Pharmacol Methods
14:
157-167,
1985[Web of Science][Medline].
21.
Palazzo, AJ,
Jones SP,
Girod WG,
Anderson DC,
Granger DN,
and
Lefer DJ.
Myocardial ischemia-reperfusion injury in CD18- and ICAM-1-deficient mice.
Am J Physiol Heart Circ Physiol
275:
H2300-H2307,
1998
22.
Read, MA,
Neish AS,
Gerritsen ME,
and
Collins T.
Postinduction transcriptional repression of E-selectin and vascular cell adhesion molecule-1.
J Immunol
157:
3472-3479,
1996[Abstract].
23.
Relton, JK,
Sloan KE,
Frew EM,
Whalley ET,
Adams SP,
and
Lobb RR.
Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats.
Stroke
32:
199-205,
2001
24.
Russell, J,
Epstein CJ,
Grisham MB,
Alexander JS,
Yeh KY,
and
Granger DN.
Regulation of E-selectin expression in postischemic intestinal microvasculature.
Am J Physiol Gastrointest Liver Physiol
278:
G878-G885,
2000
25.
Shi, J,
Ross CR,
Leto TL,
and
Blecha F.
PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47 phox.
Proc Natl Acad Sci USA
93:
6014-6018,
1996
26.
Tamiya, Y,
Yamamoto N,
and
Uede T.
Protective effect of monoclonal antibodies against LFA-1 and ICAM-1 on myocardial reperfusion injury following global ischemia in rat hearts.
Immunopharmacology
29:
53-63,
1995[Web of Science][Medline].
27.
Vos, IH,
Govers R,
Grone HJ,
Kleij L,
Schurink M,
De Weger RA,
Goldschmeding R,
and
Rabelink TJ.
NFkappaB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts.
FASEB J
14:
815-822,
2000
28.
Zhao, ZQ,
Lefer DJ,
Sato H,
Hart KK,
Jefforda PR,
and
Vinten-Johansen J.
Monoclonal antibody to ICAM-1 preserves postischemic blood flow and reduces infarct size after ischemia-reperfusion in rabbit.
J Leukoc Biol
62:
292-300,
1997[Abstract].
This article has been cited by other articles:
|
|
 |
|
  S. U. Sixt, M. Adamzik, D. Spyrka, B. Saul, J. Hakenbeck, J. Wohlschlaeger, U. Costabel, A. Kloss, J. Giesebrecht, B. Dahlmann, et al. Alveolar Extracellular 20S Proteasome in Patients with Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1098 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Willis, J. C. Schisler, A. L. Portbury, and C. Patterson Build it up-Tear it down: protein quality control in the cardiac sarcomere Cardiovasc Res, February 15, 2009; 81(3): 439 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yabe and T. Koide Inhibition of the 20S Proteosome by a Protein Proteinase Inhibitor: Evidence That a Natural Serine Proteinase Inhibitor Can Inhibit a Threonine Proteinase J. Biochem., February 1, 2009; 145(2): 217 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. S. Machado, L. Esper, A. Dias, R. Madan, Y. Gu, D. Hildeman, C. N. Serhan, C. L. Karp, and J. Aliberti Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6 J. Exp. Med., May 12, 2008; 205(5): 1077 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. C. Moss, W. E. Stansfield, M. S. Willis, R.-H. Tang, and C. H. Selzman IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2248 - H2253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. E. Stansfield, N. C. Moss, M. S. Willis, R. Tang, and C. H. Selzman Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury Ann. Thorac. Surg., July 1, 2007; 84(1): 120 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Shenoy Seven-Transmembrane Receptors and Ubiquitination Circ. Res., April 27, 2007; 100(8): 1142 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Powell The ubiquitin-proteasome system in cardiac physiology and pathology Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H1 - H19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Zolk, C. Schenke, and A. Sarikas The ubiquitin-proteasome system: Focus on the heart Cardiovasc Res, June 1, 2006; 70(3): 410 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hedhli, M. Pelat, and C. Depre Protein turnover in cardiac cell growth and survival Cardiovasc Res, November 1, 2005; 68(2): 186 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Khurana, Z. Zhuang, S. Bhardwaj, M. Murakami, E. De Muinck, S. Yla-Herttuala, N. Ferrara, J. F. Martin, I. Zachary, and M. Simons Angiogenesis-Dependent and Independent Phases of Intimal Hyperplasia Circulation, October 19, 2004; 110(16): 2436 - 2443. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
