Antioxidant tempol suppresses heart cytosolic phospholipase A2α stimulated by chronic intermittent hypoxia

2017 ◽  
Vol 95 (8) ◽  
pp. 920-927 ◽  
Author(s):  
Petra Míčová ◽  
Martina Klevstig ◽  
Kristýna Holzerová ◽  
Marek Vecka ◽  
Jitka Žurmanová ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Acute Ischemia ◽  
Left Ventricular Myocardium ◽  
Ros Generation ◽  
Mrna Levels

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia–reperfusion injury. Phospholipases A2(PLA2s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2(cPLA2α), its phosphorylated form (p-cPLA2α), calcium-independent (iPLA2), and secretory (sPLA2IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA2s expression and phospholipid FA remodeling. While CIH did not affect PLA2s mRNA levels, it increased the total cPLA2α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA2α (by 23%) in membranes. On the contrary, both iPLA2and sPLA2IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA2α up-regulation and its phosphorylation on Ser505. Our results show that CIH diversely affect myocardial PLA2s and suggest that ROS are responsible for the activation of cPLA2α under these conditions.

Increased expression and altered subcellular distribution of PKC-δ in chronically hypoxic rat myocardium: involvement in cardioprotection

2005 ◽  
Vol 288 (4) ◽  
pp. H1566-H1572 ◽  
Author(s):  
Jan Neckář ◽  
Irena Marková ◽  
František Novák ◽  
Olga Nováková ◽  
Ondrej Szárszoi ◽  
...  
Keyword(s):  
Infarct Size ◽  
Intermittent Hypoxia ◽  
Chronic Hypoxia ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Control Group ◽  
Left Ventricular Myocardium ◽  
High Dose ◽  
Area At Risk

We examined the role of protein kinase C (PKC) in the cardioprotective mechanism induced by long-term adaptation to chronic intermittent hypoxia. Adult male Wistar rats were exposed to hypobaric hypoxia of 7,000 m for 8 h/day, 5 days/wk; the total number of exposures was 24–32. A control group was kept under normoxic conditions. Western blot analysis of PKC isoforms-δ and -ε was performed in the cytosol and three particulate fractions of left ventricular myocardium. Infarct size was determined in open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion. The PKC inhibitors chelerythrine (1 or 5 mg/kg) or rottlerin (selective for PKC-δ isoform; 0.3 mg/kg) were administered intravenously as a single bolus 15 min before ischemia. Chronic hypoxia had no effect on the expression and distribution of PKC-ε. The relative amount of PKC-δ increased in the cytosol and nuclear-cytoskeletal, mitochondrial, and microsomal fractions of chronically hypoxic myocardium by 100%, 212%, 237%, and 146%, respectively, compared with corresponding normoxic values. Chronic hypoxia decreased the size of myocardial infarction (normalized to the area at risk) by about one-third on the average ( P < 0.05). Both doses of chelerythrine tended to reduce infarction in controls, and only the high dose completely abolished the improvement of ischemic tolerance in hypoxic hearts ( P < 0.05). Rottlerin attenuated the infarct size-limiting effect of chronic hypoxia ( P < 0.05), and it had no effect in controls. These results suggest that chronic intermittent hypoxia-induced cardioprotection in rats is partially mediated by PKC-δ; the contribution of other isoforms remains to be determined.

Role of oxidative stress in PKC-δ upregulation and cardioprotection induced by chronic intermittent hypoxia

2007 ◽  
Vol 292 (1) ◽  
pp. H224-H230 ◽  
Author(s):  
František Kolář ◽  
Jana Ježková ◽  
Patricie Balková ◽  
Jiří Břeh ◽  
Jan Neckář ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Infarct Size ◽  
Intermittent Hypoxia ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Ischemic Tolerance ◽  
Saline Control ◽  
Chronic Intermittent Hypoxia ◽  
Left Ventricular Myocardium ◽  
Area At Risk

The aim was to determine whether increased oxidative stress during the adaptation to chronic intermittent hypoxia (CIH) plays a role in the induction of improved cardiac ischemic tolerance. Adult male Wistar rats were exposed to CIH in a hypobaric chamber (7,000 m, 8 h/day, 5 days/wk, 24–30 exposures). Half of the animals received antioxidant N-acetylcysteine (NAC; 100 mg/kg) daily before the exposure; the remaining rats received saline. Control rats were kept under normoxia and treated in a corresponding manner. One day after the last exposure (and/or NAC injection), anesthetized animals were subject to 20 min of coronary artery occlusion and 3 h of reperfusion for determination of infarct size. In parallel subgroups, biochemical analyses of the left ventricular myocardium were performed. Adaptation to CIH reduced infarct size from 56.7 ± 4.5% of the area at risk in the normoxic controls to 27.7 ± 4.9%. NAC treatment decreased the infarct size in the controls to 42.0 ± 3.4%, but it abolished the protection provided by CIH (to 41.1 ± 4.9%). CIH decreased the reduced-to-oxidized glutathione ratio and increased the relative amount of PKC isoform-δ in the particulate fraction; NAC prevented these effects. The expression of PKC-ε was decreased by CIH and not affected by NAC. Activities of superoxide dismutase, catalase, and glutathione peroxidase were affected by neither CIH nor NAC treatment. It is concluded that oxidative stress associated with CIH plays a role in the development of increased cardiac ischemic tolerance. The infarct size-limiting mechanism of CIH seems to involve the PKC-δ-dependent pathway but apparently not the increased capacity of major antioxidant enzymes.

scholarly journals Involvement of PKCε in Cardioprotection Induced by Adaptation to Chronic Continuous Hypoxia

2015 ◽  
pp. 191-201 ◽  
Author(s):  
K. HOLZEROVÁ ◽  
M. HLAVÁČKOVÁ ◽  
J. ŽURMANOVÁ ◽  
G. BORCHERT ◽  
J. NECKÁŘ ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Mrna Levels ◽  
Inhibitory Peptide ◽  
Male Wistar Rats ◽  
Ldh Release

Continuous normobaric hypoxia (CNH) renders the heart more tolerant to acute ischemia/reperfusion injury. Protein kinase C (PKC) is an important component of the protective signaling pathway, but the contribution of individual PKC isoforms under different hypoxic conditions is poorly understood. The aim of this study was to analyze the expression of PKCε after the adaptation to CNH and to clarify its role in increased cardiac ischemic tolerance with the use of PKCε inhibitory peptide KP-1633. Adult male Wistar rats were exposed to CNH (10 % O2, 3 weeks) or kept under normoxic conditions. The protein level of PKCε and its phosphorylated form was analyzed by Western blot in homogenate, cytosolic and particulate fractions; the expression of PKCε mRNA was measured by RT-PCR. The effect of KP-1633 on cell viability and lactate dehydrogenase (LDH) release was analyzed after 25-min metabolic inhibition followed by 30-min re-energization in freshly isolated left ventricular myocytes. Adaptation to CNH increased myocardial PKCε at protein and mRNA levels. The application of KP-1633 blunted the hypoxia-induced salutary effects on cell viability and LDH release, while control peptide KP-1723 had no effect. This study indicates that PKCε is involved in the cardioprotective mechanism induced by CNH.

Silencing of sodium/hydrogen exchanger in the heart by direct injection of naked siRNA

2011 ◽  
Vol 111 (2) ◽  
pp. 566-572 ◽  
Author(s):  
Patricio E. Morgan ◽  
María V. Correa ◽  
Irene L. Ennis ◽  
Ariel A. Diez ◽  
Néstor G. Pérez ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Direct Injection ◽  
Experimental Models ◽  
Left Ventricular ◽  
Maximal Velocity ◽  
Mrna Levels ◽  
Small Interference Rna

Cardiac Na+/H+ exchanger (NHE1) hyperactivity is a central factor in cardiac remodeling following hypertension, myocardial infarction, ischemia-reperfusion injury, and heart failure. Treatment of these pathologies by inhibiting NHE1 is challenging because specific drugs that have been beneficial in experimental models were associated with undesired side effects in clinical practice. In the present work, small interference RNA (siRNA) produced in vitro to specifically silence NHE1 (siRNANHE1) was injected once in vivo into the apex of the left ventricular wall of mouse myocardium. After 48 h, left ventricular NHE1 protein expression was reduced in siRNANHE1-injected mice compared with scrambled siRNA by 33.2 ± 3.4% ( n = 5; P < 0.05). Similarly, NHE1 mRNA levels were reduced by 20 ± 2.0% ( n = 4). At 72 h, siRNANHE1 spreading was evident from the decrease in NHE1 expression in three portions of the myocardium (apex, medium, base). NHE1 function was assessed based on maximal velocity of intracellular pH (pHi) recovery (dpHi/d t) after an ammonium prepulse-induced acidic load. Maximal dpHi/d t was reduced to 14% in siRNANHE1-isolated left ventricular papillary muscles compared with scrambled siRNA. In conclusion, only one injection of naked siRNANHE1 successfully reduced NHE1 expression and activity in the left ventricle. As has been previously suggested, extensive NHE1 expression reduction may indicate myocardial spread of siRNA molecules from the injection site through gap junctions, providing a valid technique not only for further research into NHE1 function, but also for consideration as a potential therapeutic strategy.

IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

2007 ◽  
Vol 293 (4) ◽  
pp. H2248-H2253 ◽  
Author(s):  
Nancy C. Moss ◽  
William E. Stansfield ◽  
Monte S. Willis ◽  
Ru-Hang Tang ◽  
Craig H. Selzman
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Nuclear Factor Κb ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Artery Ligation ◽  
Cardiac Morbidity

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

2012 ◽  
Vol 90 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Sri N. Batchu ◽  
Stephen B. Lee ◽  
Victor Samokhvalov ◽  
Ketul R. Chaudhary ◽  
Haitham El-Sikhry ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Left Ventricular ◽  
Ros Generation ◽  
The Novel ◽  
Active Metabolites ◽  
Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

Abstract 11685: Early Myocardial Gene Expression Profiling After Deep Hypothermic Circulatory Arrest Reveals Ontogenetic Adaptive Mechanisms Underlying Ischemia-Reperfusion Tolerance in the Swine

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Miki Yamada ◽  
Amir Sheikh ◽  
Kevin Collins ◽  
James Frederiksen ◽  
George Quick ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Circulatory Arrest ◽  
Expression Patterns ◽  
Ventricular Myocardium ◽  
Deep Hypothermic Circulatory Arrest ◽  
Left Ventricular ◽  
Hypothermic Circulatory Arrest ◽  
Left Ventricular Myocardium

Previous studies suggest that immature hearts are more tolerant to ischemia than adult myocardium; whether differences exist during ontogenic development in severity of global myocardial ischemia/reperfusion (I/R) injury associated with cardiac surgery remains unknown. We employed swine models of deep hypothermic circulatory arrest (DHCA) to test the hypothesis that early differential regulation of cardioprotective genes is associated with increased tolerance of neonatal myocardium to surgical I/R. Male neonatal and adult pigs were randomized to DHCA or sham (N=5-14/group). DHCA animals underwent cardiopulmonary bypass (18°C), DHCA 60 min, and were recovered for 3h. Severity of perioperative myocardial injury was determined biochemically (Troponin I) and echocardiographically. Transcript levels were quantified in left ventricular myocardium using Affymetrix Porcine Genome arrays, followed by differential expression and pathway analysis. A 2-fold increase in severity of perioperative myocardial injury was found in adult pigs (Fig.A). Of 596 transcripts differentially expressed in neonates (≥1.5-fold change, DHCA vs. sham, FDR<0.05), 53 were shared with adults (Fig.B). Among them, divergent expression patterns were found for oxysterol binding protein-like 6 (down-regulated in adults up-regulated in neonates) and bromodomain adjacent to zinc finger domain 2B (up-regulated in adults - down-regulated in neonates). Top transcripts uniquely upregulated in neonates but unchanged in adults were the apoptosis inhibitor baculoviral IAP repeat containing 2, and signal transducer and activator of transcription 3. mTOR signaling and p53 signaling were the top canonical pathways deregulated in adults and neonates, respectively. A high resistance to surgical I/R injury in neonatal vs adult swine heart is correlated with robust differences in early transcriptional programs, suggesting the involvement of fundamental adaptive ontogenetic processes.

Abstract 19837: DJ-1/Park7 Protects the Heart Against Ischemia-reperfusion Injury Through the Modulation of SUMOylation (Best of Basic Science Abstract)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuuki Shimizu ◽  
Larry Barr ◽  
Travis Fields ◽  
John W Calvert
Keyword(s):  
Protein Expression ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Modified Proteins

Background: DJ-1/Park7 is a ubiquitously expressed protein typically associated with the development of early onset Parkinson’s disease. Recent data suggests that it also plays a role in the cellular response to stress. Although much is known about DJ-1 in the brain, very little has been investigated in the heart. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following the onset of myocardial ischemia-reperfusion (I/R) injury. Methods and Results: Wild-type (WT) control and DJ-1 deficient (DJ-1 KO) mice were subjected to in vivo myocardial I/R injury. DJ-1 KO mice (n=9) displayed increased areas of infarction (%INF/LV or AAR: 30.2 vs 22.0%, 53.6 vs 39.0%, Troponin-I: 47.4 vs 19.9ng/ml, p<0.05 respectively) and worsened left ventricular function (LVEF: 43.7 vs 58.1%, p<0.001) when compared to WT mice (n=9), confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process which regulates various aspects of protein function, including transcription, subcellular localization, DNA repair, and cell cycle. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins, (this modification is generally associated with cell injury), and reduced SUMO-2/3 modified proteins (this modification is generally associated with cytoprotection). Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP-1 (removes SUMO-1 modifications) was reduced, whereas the expression of SENP-5 (removes SUMO-2/3 modifications) was enhanced in DJ-1 KO hearts after I/R injury. Changes in mRNA levels did not account for the altered protein expression of SENP-1 and SENP-5. So, we evaluated the direct interaction of DJ-1 with both proteins in hearts of WT mice following I/R using co-immunoprecipitation. We found that SENP1 binding with DJ-1 was down-regulated, whereas SENP5 binding with DJ-1 was up-regulated. Conclusion: Our data demonstrated that the activation of DJ-1 in response to myocardial I/R injury protects the heart by the modulation of SUMOylation via direct binding of SENP1 and SENP5.

Abstract 3013: Myocardium at Risk of Infarction during Acute Ischemia is Accurately Measured after Revascularization by MRI in Humans

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Marcus Carlsson ◽  
Erik Hedstrom ◽  
Einar Heiberg ◽  
Hakan Arheden
Keyword(s):  
At Risk ◽  
Visual Assessment ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Left Ventricular Myocardium ◽  
Myocardium At Risk ◽  
St Elevation ◽  
The Difference ◽  
First Time

PURPOSE: The size of an infarct caused by coronary occlusion mainly depends on the duration of ischemia and the size of the ischemic myocardium, called myocardium at risk (MaR). T2-STIR imaging (visualizing oedema) has been shown to depict MaR in dogs. However, this has not been validated in humans. Therefore the purpose of this study was to validate the measurement of MaR by MRI against SPECT. METHODS: 7 patients (69±8 years, all male) with ST-elevation infarction treated by PCI were included. Technetium-labelled tetrofosmin was injected during ongoing ischemia before opening of the occluded vessel. SPECT was performed after concluded PCI and cardiac MRI after 3±3 days. MaR was measured as absent perfusion on SPECT and oedema on MRI, and expressed in percent of the left ventricular myocardium. The observer of the MRI data was blinded to the SPECT results. The localisation of transmural ischemia by the two methods was compared by visual assessment. RESULTS: The difference between SPECT and MRI for measurement of MaR was 0±9 % (mean±SD). The localization of transmural ischemia agreed between the two methods (Fig. 1 ) and expressed on vessel basis, MRI and SPECT showed 100 % concordant results. CONCLUSIONS: This study has showed for the first time in humans that T2-STIR accurately can determine myocardium at risk. This can be used in clinical research when studying new therapies for reducing infarct size. Fig 1 : Short axis slices of left ventricle showing inferior defect on SPECT (arrows, left panel) corresponding to the oedema signal on T2-STIR MRI (arrows, middle panel). For comparison, delayed enhancement in right panel shows subendocardial infarction (arrows).

Ischemia–reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli

2005 ◽  
Vol 83 (3) ◽  
pp. 287-300 ◽  
Author(s):  
Annick Caron ◽  
Richard R Desrosiers ◽  
Stéphanie Langlois ◽  
Richard Béliveau
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Gelatin Zymography ◽  
Acute Ischemia ◽  
Mrna Levels ◽  
Gelatinase Activity ◽  
Stimulation Of

Although ischemia remains the leading cause of acute renal failure in humans, there is little information on the expression and activities of gelatinases of kidney glomeruli during ischemia–reperfusion injury. In this study, we used a unilateral ischemia–reperfusion model to investigate the activity and expression of gelatinases in glomeruli during acute ischemia. Unilateral ischemia was induced in rats by vascular clamping (30 min) followed by reperfusion (60 min) and isolation of glomeruli. The activity and expression of gelatinase proteins were determined by gelatin zymography and Western blotting. Gelatinase mRNA levels were evaluated by reverse transciptase-PCR. Ischemia and reperfusion increased serum creatinine levels, hallmark of acute renal failure. Ischemia induced mRNA and protein MMP-2 expression. There was strong stimulation of MMP-9 mRNA, both forms of dimeric MMP-9, and active mono meric MMP-9. In contrast to TIMP-1 decreasing, TIMP-2 protein and mRNA increased during ischemia. During reperfusion, there was a gradual reversal of the MMP-2 and MMP-9 levels and a strong inhibition of TIMP-1 and TIMP-2 at the protein and mRNA levels. Endocytic receptor LRP was increased during ischemia and returned to normal during reperfusion. Expression of MMP-9 docking receptor CD-44 was increased during reperfusion. Finally, ZO-1, an in vivo MMP-9 substrate, was degraded during ischemia, revealing that MMP-9 upregulated during ischemia was functional. Our data suggest that stimulation of gelatinase activity during ischemia could contribute to glomeruli injury, providing new therapeutic targets for acute renal failure in humans. In contrast, elevated monomeric MMP-9 activity due to TIMP-1 decrease during reperfusion may participate to glomerular recovery.Key words: gelatinases, ischemia-reperfusion, TIMPs, ZO-1, CD-44, LRP, glomeruli.

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