PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated IκBα degradation

2001 ◽  
Vol 281 (6) ◽  
pp. H2612-H2618 ◽  
Author(s):  
Jialin Bao ◽  
Kaori Sato ◽  
Min Li ◽  
Youhe Gao ◽  
Ruhul Abid ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Adhesion Molecule ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Myeloperoxidase Activity ◽  
Intramyocardial Injection ◽  
Iκbα Degradation

PR-39 inhibits proteasome-mediated IκBα 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 IκBα 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/d t) 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 IκBα degradation and subsequent inhibition of nuclear factor-κB-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.

Rosuvastatin reduces experimental left ventricular infarct size after ischemia-reperfusion injury but not total coronary occlusion

2005 ◽  
Vol 288 (4) ◽  
pp. H1802-H1809 ◽  
Author(s):  
Ellen O. Weinberg ◽  
Marielle Scherrer-Crosbie ◽  
Michael H. Picard ◽  
Boris A. Nasseri ◽  
Catherine MacGillivray ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Protection ◽  
Coronary Occlusion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Saline Group ◽  
Left Ventricular ◽  
Deficient Mice

This study compared the effects of rosuvastatin on left ventricular infarct size in mice after permanent coronary occlusion vs. 60 min of ischemia followed by 24 h of reperfusion. Statins can inhibit neutrophil adhesion, increase nitric oxide synthase (NOS) expression, and mobilize progenitor stem cells after ischemic injury. Mice received blinded and randomized administration of rosuvastatin (20 mg·kg−1·day−1) or saline from 2 days before surgery until death. After 60 min of ischemia with reperfusion, infarct size was reduced by 18% ( P = 0.03) in mice randomized to receive rosuvastatin ( n = 18) vs. saline ( n = 22) but was similar after permanent occlusion in rosuvastatin ( n = 17) and saline ( n = 20) groups ( P = not significant). Myocardial infarct size after permanent left anterior descending coronary artery occlusion ( n = 6) tended to be greater in NOS3-deficient mice than in the wild-type saline group (33 ± 4 vs. 23 ± 2%, P = 0.08). Infarct size in NOS3-deficient mice was not modified by treatment with rosuvastatin (34 ± 5%, n = 6, P = not significant vs. NOS3-deficient saline group). After 60 min of ischemia-reperfusion, neutrophil infiltration was similar in rosuvastatin and saline groups as was the percentage of CD34+, Sca-1+, and c-Kit+ cells. Left ventricular NOS3 mRNA and protein levels were unchanged by rosuvastatin. Rosuvastatin reduces infarct size after 60 min of ischemia-reperfusion but not after permanent coronary occlusion, suggesting a potential anti-inflammatory effect. Although we were unable to demonstrate that the myocardial protection was due to an effect on neutrophil infiltration, stem cell mobilization, or induction of NOS3, these data suggest that rosuvastatin may be particularly beneficial in myocardial protection after ischemia-reperfusion injury.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

Blocking Na+/H+ exchange reduces [Na+]i and [Ca2+]i load after ischemia and improves function in intact hearts

2001 ◽  
Vol 281 (6) ◽  
pp. H2398-H2409 ◽  
Author(s):  
Jianzhong An ◽  
Srinivasan G. Varadarajan ◽  
Amadou Camara ◽  
Qun Chen ◽  
Enis Novalija ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ringer Solution ◽  
Left Ventricular ◽  
Isolated Hearts ◽  
Intracellular Ca ◽  
Ionic Basis

We determined in intact hearts whether inhibition of Na+/H+ exchange (NHE) decreases intracellular Na+ and Ca2+ during ischemia and reperfusion, improves function during reperfusion, and reduces infarct size. Guinea pig isolated hearts were perfused with Krebs-Ringer solution at 37°C. Left ventricular (LV) free wall intracellular Na+ concentration ([Na+]i) and intracellular Ca2+ concentration ([Ca2+]i) were measured using fluorescence dyes. Hearts were exposed to 30 min of ischemia with or without 10 μM of benzamide (BIIB-513), a selective NHE-1 inhibitor, infused for 10 min just before ischemia or for 10 min immediately on reperfusion. At 2 min of reperfusion, BIIB-513 given before ischemia decreased peak increases in [Na+]i and [Ca2+]i, respectively, from 2.5 and 2.3 times (controls) to 1.6 and 1.3 times preischemia values. At 30 min of reperfusion, BIIB-513 increased systolic-diastolic LV pressure (LVP) from 49 ± 2% (controls) to 80 ± 2% of preischemia values. BIIB-513 reduced ventricular fibrillation by 54% and reduced infarct size from 64 ± 1% to 20 ± 3%. First derivative of the LVP, O2 consumption, and cardiac efficiency were also improved by BIIB-513. Similar results were obtained with BIIB-513 given on reperfusion. These data show that Na+ loading is a marker of reperfusion injury in intact hearts in that inhibiting NHE reduces Na+ and Ca2+ loading during reperfusion while improving function. These results clearly implicate the ionic basis by which inhibiting NHE protects the guinea pig intact heart from ischemia-reperfusion injury.

Differential contribution of necrosis and apoptosis in myocardial ischemia-reperfusion injury

2004 ◽  
Vol 286 (5) ◽  
pp. H1923-H1935 ◽  
Author(s):  
James D. McCully ◽  
Hidetaka Wakiyama ◽  
Yng-Ju Hsieh ◽  
Mara Jones ◽  
Sidney Levitsky
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Injury ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Parp Cleavage ◽  
Control Group ◽  
Early Reperfusion

Necrosis and apoptosis differentially contribute to myocardial injury. Determination of the contribution of these processes in ischemia-reperfusion injury would allow for the preservation of myocardial tissue. Necrosis and apoptosis were investigated in Langendorff-perfused rabbit hearts ( n = 47) subjected to 0 (Control group), 5 (GI-5), 10 (GI-10), 15 (GI-15), 20 (GI-20), 25 (GI-25), and 30 min (GI-30) of global ischemia (GI) and 120 min of reperfusion. Myocardial injury was determined by triphenyltetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), bax, bcl2, poly(ADP)ribose polymerase (PARP) cleavage, caspase-3, -8, and -9 cleavage and activity, Fas ligand (FasL), and Fas-activated death domain (FADD). The contribution of apoptosis was determined separately ( n = 42) using irreversible caspase-3, -8, and -9 inhibitors. Left ventricular peak developed pressure (LVPDP) and systolic shortening (SS) were significantly decreased and infarct size and TUNEL-positive cells were significantly increased ( P < 0.05 vs. Control group) at GI-20, GI-25, and GI-30. Proapoptotic bax, PARP cleavage, and caspase-3 and -9 cleavage and activity were apparent at GI-5 to GI-30. Fas, FADD, and caspase-8 cleavage and activity were unaltered. Irreversible inhibition of caspase-3 and -9 activity significantly decreased ( P < 0.05) infarct size at GI-25 and GI-30 but had no effect on LVPDP or SS. Myocardial injury results from a significant increase in both necrosis and apoptosis ( P < 0.05 vs. Control group) evident by TUNEL, TTC staining, and caspase activity at GI-20. Intrinsic proapoptotic activation is evident early during ischemia but does not significantly contribute to infarct size before GI-25. The contribution of necrosis to infarct size at GI-20, GI-25, and GI-30 is significantly greater than that of apoptosis. Apoptosis is significantly decreased by caspase inhibition during early reperfusion, but this protection does not improve immediate postischemic functional recovery.

scholarly journals Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia

2011 ◽  
Vol 300 (6) ◽  
pp. H2308-H2315 ◽  
Author(s):  
Raffaella Rastaldo ◽  
Sandra Cappello ◽  
Anna Folino ◽  
Giovanni N. Berta ◽  
Andrea E. Sprio ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Protein Level ◽  
Ischemia Reperfusion Injury ◽  
Recovery Of Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Risk Area ◽  
Early Reperfusion ◽  
Mechanical Recovery

We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre- or postconditioning mimetic and whether the improved postischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor (APJ) plays a role in cardioprotection. Langendorff-perfused rat hearts underwent 30 min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and lactate dehydrogenase release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 μM concentration for 20 min either before ischemia or in early reperfusion, without and with NO synthase inhibition by NG-nitro-l-arginine (l-NNA). In additional experiments, before ischemia also 1 μM apelin-13 was tested. APJ protein level was measured before and after ischemia. Whereas before ischemia apelin-13 (0.5 and 1.0 μM) was ineffective, after ischemia it reduced infarct size from 54 ± 2% to 26 ± 4% of risk area ( P < 0.001) and limited the postischemic myocardial contracture ( P < 0.001). l-NNA alone increased postischemic myocardial contracture. This increase was attenuated by apelin-13, which, however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min perfusion, i.e., after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level.

Isoflurane Produces Sustained Cardiac Protection after Ischemia–Reperfusion Injury in Mice

2006 ◽  
Vol 104 (3) ◽  
pp. 495-502 ◽  
Author(s):  
Yasuo M. Tsutsumi ◽  
Hemal H. Patel ◽  
N Chin Lai ◽  
Toshiyuki Takahashi ◽  
Brian P. Head ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Adenosine Triphosphate ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Cardiac Protection ◽  
Intact Mouse

Background Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Methods Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Results Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Conclusions Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after ischemia-reperfusion injury in mice in vivo.

Long-term effect of low energy laser irradiation on infarction and reperfusion injury in the rat heart

2001 ◽  
Vol 90 (6) ◽  
pp. 2411-2419 ◽  
Author(s):  
Tali Yaakobi ◽  
Yariv Shoshany ◽  
Sara Levkovitz ◽  
Ofer Rubin ◽  
Shlomo A. Ben Haim ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Laser Irradiation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Low Energy ◽  
Energy Laser ◽  
Low Energy Laser

Low-energy laser irradiation (LELI) has been found to modulate biological processes. The present study investigated the effect of LELI on infarct size after chronic myocardial infarction (MI) and ischemia-reperfusion injury in rats. The left anterior descending (LAD) coronary artery was ligated in 83 rats to create MI or ischemia-reperfusion injury. The hearts of the laser-irradiated (LI) rats received irradiation after LAD coronary artery occlusion and 3 days post-MI. At 14, 21, and 45 days post-LAD coronary artery permanent occlusion, infarct sizes (percentage of left ventricular volume) in the non-laser-irradiated (NLI) rats were 52 ± 12 (SD), 47 ± 11, and 34 ± 7%, respectively, whereas in the LI rats they were significantly lower, being 20 ± 8, 15 ± 6, and 10 ± 4%, respectively. Left ventricular dilatation (LVD) in the chronic infarcted rats was significantly reduced (50–60%) in LI compared with NLI rats. LVD in the ischemia-reperfusion-injured LI rats was significantly reduced to a value that did not differ from intact normal noninfarcted rats. Laser irradiation caused a significant 2.2-fold elevation in the content of inducible heat shock proteins (specifically HSP70i) and 3.1-fold elevation in newly formed blood vessels in the heart compared with NLI rats. It is concluded that LELI caused a profound reduction in infarct size and LVD in the rat heart after chronic MI and caused complete reduction of LVD in ischemic-reperfused heart. This phenomenon may be partially explained by the cardioprotective effect of the HSP70i and enhanced angiogenesis in the myocardium after laser irradiation.

Crocin-Elicited Autophagy Rescues Myocardial Ischemia/Reperfusion Injury via Paradoxical Mechanisms

2016 ◽  
Vol 44 (03) ◽  
pp. 515-530 ◽  
Author(s):  
Chao Zeng ◽  
Hu Li ◽  
Zhiwen Fan ◽  
Lei Zhong ◽  
Zhen Guo ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Ischemia And Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Apoptosis And Necrosis

Crocin, the main effective component of saffron, exerts protective effects against ischemia/reperfusion injury during strokes. However, the effects of crocin in myocardial ischemia/reperfusion injury, and the mechanisms involved, remain unknown. Pretreated with crocin for 7 days, C57BL/6N mice were subjected to 30 min of myocardial ischemia followed by 12[Formula: see text]h of reperfusion (for cardiac function and infarct size, cell apoptosis and necrosis). Neonatal mouse cardiomyocytes were subjected to 2 h of hypoxia followed by 4 h of reoxygenation. NMCM’s survival was assessed during hypoxia and reoxygenation in the presence or absence of the autophagy inhibitor 3-methyladenine or the inducer rapamycin. Western blotting was used to evaluate AMPK, Akt, and autophagy-related proteins. Autophagosome was observed using electron microscopy. In the in vivo experiment, crocin pretreatment significantly attenuated infarct size, myocardial apoptosis and necrosis, and improved left ventricular function following ischemia/reperfusion. In vitro data revealed that autophagy was induced during hypoxia, the levels of which were intensely elevated during reoxygenation. Crocin significantly promoted autophagy during ischemia, accompanied with the activation of AMPK. In contrast, crocin overtly inhibited autophagy during reperfusion, accompanied with Akt activation. Induction and inhibition of autophagy mitigated crocin induced protection against NMCMs injury during hypoxia and reoxygenation, respectively. Our data suggest that crocin demonstrated a myocardial protective effect via AMPK/mTOR and Akt/mTOR regulated autophagy against ischemia and reperfusion injury, respectively.

scholarly journals Inhibition of Type 2 Sodium-Glucose Transporters and Na+/H+ Exchanger-1 produces similar cardioprotective effects in response to ischemiareperfusion injury

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Bianca S. Blaettner ◽  
Hana E. Baker ◽  
Adam G. Goodwill ◽  
Hannah E. Clark ◽  
Michael C. Kozlowski ◽  
...  
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Transporters ◽  
Left Ventricular ◽  
Area At Risk ◽  
Cardioprotective Effects

Background and Hypothesis: Recent studies indicate that inhibition of Type 2 Sodium-Glucose Transporters (SGLT2i) augments diastolic filling volume and mitigates myocardial ischemic injury. This study tested the hypothesis that inhibition of the Na+/H+ Exchanger-1 (NHE-1) mimics the cardioprotective effects of SGLT2i in response to ischemia-reperfusion injury. Experimental Design or Project Methods: Lean swine (~50 kg) were anesthetized, a thoracotomy performed, and perivascular flow transducers placed around the left anterior descending (LAD) and circumflex coronary (LCX) arteries. A pressure-volume (PV) catheter was then inserted into the left ventricle. Swine received a 15 min infusion of vehicle (DMSO; n = 3), the SGLT2i Canagliflozin (30 µM; n = 3), or the NHE-1 inhibitor Cariporide (1µM; n = 3) prior to a 60 min total occlusion of the LCX and 2-hour reperfusion period. Following reperfusion, the LCX was re-occluded and a 2.5% Patent Blue 5 solution was administered to identify area at risk. The heart was excised, sectioned, and incubated in a 2,3,5-triphenyltetrazolium chloride (TTC) solution. Images were collected and analyzed for area at risk and infarct size. Results: In the vehicle treated group, 2 of the 3 swine studied died prematurely before the completion of the protocol; one at baseline and one during ischemia. Our initial findings support that left ventricular end diastolic volume increases in response to regional myocardial ischemia in swine that received either Canagliflozin or Cariporide. This increase in diastolic volume was associated with an increase in stroke volume (i.e. Frank-Starling effect) and a reduction in myocardial infarct size in both treatment groups. Blood pressure tended to decrease to a similar extent in all groups. Conclusion and Potential Impact: These pilot studies suggest that inhibition of SGLT2 and NHE-1 produces similar functional and protective effects in response to regional ischemia-reperfusion injury. Further experiments are needed to corroborate these findings and examine the extent to which SGLT2i directly modulates NHE-1 activity.

scholarly journals pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

2015 ◽  
Vol 227 (3) ◽  
pp. 167-178 ◽  
Author(s):  
T Pasqua ◽  
B Tota ◽  
C Penna ◽  
A Corti ◽  
M C Cerra ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Chromogranin A ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Protective Effects ◽  
Perfused Heart ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-serpinin (pGlu-Serp) are positive cardiac β-adrenergic-like modulators, acting through β1-AR/AC/cAMP/PKA pathway. Because in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition, cardioprotection is often blunted because of the limitations on pro-survival Reperfusion Injury Salvage Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, left ventricular developed pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/Akt, MitoKATP channels and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 cells with pGlu-Serp, which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes that can limit infarct size and overcome the hypertension-induced failure of PostC.

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