scholarly journals Clec4e signalling influences left-ventricular functional recovery in a murine model of myocardial ischemia-reperfusion injury

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Veltman ◽  
H Gillijns ◽  
E Caluwe ◽  
M Wu ◽  
M Vanhaverbeke ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Inflammatory Response ◽  
Functional Recovery ◽  
Gene Deletion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Funding Source ◽  
Acute Inflammatory Response ◽  
Wild Type

Abstract Introduction The acute inflammatory response contributes substantially to functional recovery and remodelling of the left ventricle after acute ischemic injury. Previously, we have shown that the C-Type Lectin Receptor CLEC4E plays a role in early leukocyte recruitment during the acute inflammatory response of ischemia-reperfusion injury (I/R). However, the role of CLEC4E signalling in functional recovery of the left ventricle after I/R remains unknown. Therefore, we studied the chronic inflammatory response and left-ventricular remodelling in murine gene deletion model of Clec4e, subjected to I/R. Methods In anesthetized C57Bl6/J wild-type (n=14) and Clec4e−/− (n=13) mice, we transiently occluded the left-descending artery for 60 min, followed by 4 weeks reperfusion (I/R). A blood sample was collected at 90 minutes reperfusion to measure high-sensitivity troponin I (TnI) levels, as a surrogate marker of cardiac damage. At 4 weeks, mice underwent MRI (7T) to investigate the effect of Clec4e-gene deletion on LV-remodelling. Results Plasma TnI-levels showed no statistical difference between both groups, indicating that the initial insult was comparable. In wild-type mice, plasma TnI-levels negatively correlated with ejection fraction (EF, R2=0.92 p<0.0001) at 4 weeks I/R, while Clec4e−/− mice showed preserved EF, irrespective of 90 minutes TnI-levels. MRI-analysis at 4 weeks after I/R showed significantly smaller end-diastolic and end-systolic volumes in Clec4e−/− mice, together with a trend towards a higher ejection fraction, suggesting better preserved structural and functional LV-remodelling (Fig.1). Conclusion The inflammatory leukocyte-associated Clec4e signalling pathway impairs functional recovery of the left ventricle after myocardial I/R injury. Inhibition of the Clec4e receptor may be a promising strategy in the treatment of ischemic injury. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Scholarship Ir. Jozef en Mevr. Reinhilde De Swerts 2018-2022 by the Royal Academy of Medicine of Belgium

scholarly journals Inhibition of Myocardial Ischemia/Reperfusion Injury by Exosomes Secreted from Mesenchymal Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Heng Zhang ◽  
Meng Xiang ◽  
Dan Meng ◽  
Ning Sun ◽  
Sifeng Chen
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Left Ventricle ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Area At Risk

Exosomes secreted by mesenchymal stem cells have shown great therapeutic potential in regenerative medicine. In this study, we performed meta-analysis to assess the clinical effectiveness of using exosomes in ischemia/reperfusion injury based on the reports published between January 2000 and September 2015 and indexed in the PUBMED and Web of Science databases. The effect of exosomes on heart function was evaluated according to the following parameters: the area at risk as a percentage of the left ventricle, infarct size as a percentage of the area at risk, infarct size as a percentage of the left ventricle, left ventricular ejection fraction, left ventricular fraction shortening, end-diastolic volume, and end-systolic volume. Our analysis indicated that the currently available evidence confirmed the therapeutic potential of mesenchymal stem cell-secreted exosomes in the improvement of heart function. However, further mechanistic studies, therapeutic safety, and clinical trials are required for optimization and validation of this approach to cardiac regeneration after ischemia/reperfusion injury.

scholarly journals Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo

2008 ◽  
Vol 295 (5) ◽  
pp. H2128-H2134 ◽  
Author(s):  
Atsuko Motoki ◽  
Matthias J. Merkel ◽  
William H. Packwood ◽  
Zhiping Cao ◽  
Lijuan Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury.

Nanoparticles loaded with hepatic growth factor and insulin-like growth factor-1 improve left ventricular repair in a porcine model of myocardial Ischemia reperfusion injury

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Wu ◽  
P Claus ◽  
S De Buck ◽  
D Veltman ◽  
H Gillijns ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Funding Source ◽  
Insulin Like Growth Factor ◽  
Infarct Zone ◽  
Intramyocardial Injection ◽  
Flow Reserve ◽  
Lv Mass

Abstract Introduction Nanomedicine offers great potential for treatment of cardiovascular disease. We tested whether intramyocardial (IM) injection of pro-angiogenic hepatocyte growth factor (HGF) and anti-apoptotic, pro-myogenic insulin-like growth factor 1 (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) improves left ventricular (LV) functional recovery in a porcine ischemia-reperfusion (I/R) model. Methods Myocardial infarction (MI) was induced by 75min balloon occlusion of the mid-LAD followed by reperfusion. After 1w, pigs (n=12) with marked LV dysfunction (EF<45%) were randomized to fusion imaging-guided IM injections of 8 mg Cy5-labelled AlgS-NP loaded with 200μg HGF and IGF-1 (GF) or with phosphate-buffered saline (CON) using the MYOSTAR injection catheter. AlgS-NP retention in the heart was determined by measuring Cy5 levels in peripheral blood. At 8w, treatment effect was evaluated using cardiac magnetic resonance imaging and coronary flow reserve (CFR) measurements, and further assessed using sirius red staining to measure myocardial fibrosis. Results At 1w after MI, LV ejection frqction (LVEF) was 37±5% (range 27–45%) and infarct size (IS)/LV mass 24±6% (range 19–38%). Myocardial retention of AlgS-NP was comparable between 2 groups (maximal systemic leakage after IM injection: 9% CON vs 20% GF, P=0.25). After 8 w, IS/LV mass decreased by one third in GF-treated pigs compared with 14% in CON (P=0.03, Fig. A) and was associated with a trend towards improvement in CFR (P=0.05, Fig. B). LVEF significantly increased in GF-treated pigs (6±2% vs. −1±1%, P=0.02, Fig. C), which was attributable to a greater reduction in end-systolic volume. The improvement in LVEF was also consistent with significant reduction of fibrosis (P=0.01, Fig. D) in the peri-infarct zone (PI). Conclusions Intramyocardial injection of AlgS-nanoparticle-encapsulated HGF and IGF-1 to the ischemic myocardium significantly improves LV repair, and offers the prospect of innovative treatment for patients with refractory ischemic heart disease. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): EuroNanoMed, Horizon 2020

scholarly journals Enhanced Activity by NKCC1 and Slc26a6 Mediates Acidic pH and Cl− Movement after Cardioplegia-Induced Arrest of db/db Diabetic Heart

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Minjeong Ji ◽  
Seok In Lee ◽  
Sang Ah Lee ◽  
Kuk Hui Son ◽  
Jeong Hee Hong
Keyword(s):  
Left Ventricle ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Heart ◽  
Ion Transporters ◽  
Cardioplegic Arrest ◽  
Wild Type ◽  
Cardiac Tissues ◽  
Enhanced Expression ◽  
Ion Imbalance

Diabetic heart dysfunctions during cardiac surgeries have revealed several clinical problems associated with ion imbalance. However, the mechanism of ion imbalance mediated by cardioplegia and a diabetic heart is largely unclear. We hypothesized that ion transporters might be regulated differently in the diabetic heart and that the differentially regulated ion transporters may involve in ion imbalance of the diabetic heart after cardioplegic arrest. In this study, we modified the Langendorff-free cardioplegia method and identified the involved ion transporters after cardioplegia-induced arrest between wild type and db/db heart. Enhanced expression of Na+-K+-2Cl− cotransporter 1 (NKCC1) was observed in the db/db heart compared to the wild type heart. Enhanced NKCC1 activity was observed in the left ventricle of db/db mice compared to that of wild type after cardioplegia-induced arrest. The expression and activity of Slc26a6, a dominant Cl−/HCO3− exchanger in cardiac tissues, were enhanced in left ventricle strips of db/db mice compared to that of wild type. The Cl− transporting activity in left ventricle strips of db/db mice was dramatically increased as compared to that of wild type. Interestingly, expression of Slc26a6, as well as carbonic anhydrase IV as a supportive enzyme of Slc26a6, was increased in db/db cardiac strips compared to wild type cardiac strips. Thus, the enhanced Cl− transporting activity and expression by NKCC1 and Slc26a6 in db/db cardiac tissues after cardioplegia-induced arrest provide greater insight into enhanced acidosis and Cl− movement-mediated db/db heart dysfunction. Thus, we suggested that enhanced Cl− influx and HCO3− efflux through NKCC1 and Slc26a6 offer more acidic circumstances in the diabetic heart after cardioplegic arrest. These transporters should be considered as potential therapeutic targets to develop the next generation of cardioplegia solution for protection against ischemia-reperfusion injury in diabetic hearts.

ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1650-1653 ◽  
Author(s):  
Masayuki Fujioka ◽  
Kazuhide Hayakawa ◽  
Kenichi Mishima ◽  
Ai Kunizawa ◽  
Keiichi Irie ◽  
...  
Keyword(s):  
Brain Damage ◽  
Gene Deletion ◽  
Ischemia Reperfusion Injury ◽  
Thrombus Formation ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Ischemic Brain Damage ◽  
Ischemic Brain

Abstract Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib–von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13−/− and wild-type mice. After reperfusion for 0.5 hours, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13−/− mice compared with wild-type mice (P < .05), which also resulted in a larger infarct volume after 24 hours for Adamts13−/− compared with wild-type mice (P < .01). Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interactions after reperfusion. These results indicate that ADAMTS13 may be a useful therapeutic agent for stroke.

Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury

2007 ◽  
Vol 292 (1) ◽  
pp. H503-H509 ◽  
Author(s):  
Yasushi Sakata ◽  
Jian-Wen Dong ◽  
Jesus G. Vallejo ◽  
Chien-Hua Huang ◽  
J. Scott Baker ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Lv Dysfunction ◽  
Toll Like Receptor 2 ◽  
Myocardial Ischemia Reperfusion

Production of proinflammatory cytokines contributes to cardiac dysfunction during ischemia-reperfusion. The principal mechanism responsible for the induction of this innate stress response during periods of myocardial ischemia-reperfusion remains unknown. Toll-like receptor 2 (TLR2) is a highly conserved pattern recognition receptor that has been implicated in the innate immune response to a variety of pathogens. However, TLR2 may also mediate inflammation in response to noninfectious injury. We therefore hypothesized that TLR2 is essential for modulating myocardial inflammation and left ventricular (LV) function during ischemia-reperfusion injury. Susceptibility to myocardial ischemia-reperfusion injury following ischemia-reperfusion was determined in Langendorff-perfused hearts isolated from wild-type mice and mice deficient in TLR2 (TLR2D) and Toll interleukin receptor domain-containing adaptor protein. After ischemia-reperfusion, contractile performance was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of LV developed pressure relative to TLR2D hearts. Creatinine kinase levels were similar in both groups after reperfusion. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNF and IL-1β. Ischemia-reperfusion-induced LV dysfunction was reversed by treatment with the recombinant TNF blocking protein etanercept. These studies show for the first time that TLR2 signaling importantly contributes to the LV dysfunction that occurs following ischemia-reperfusion. Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.

Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion

2005 ◽  
Vol 289 (5) ◽  
pp. G969-G976 ◽  
Author(s):  
Charles C. Caldwell ◽  
Tomohisa Okaya ◽  
Andre Martignoni ◽  
Thomas Husted ◽  
Rebecca Schuster ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Recruitment ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Hepatic Ischemia ◽  
Activated Neutrophils ◽  
Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion results in an acute inflammatory response culminating in the recruitment of activated neutrophils that directly injure hepatocytes. Recent evidence suggests that CD4+ lymphocytes may regulate this neutrophil-dependent injury, but the mechanisms by which this occurs remain to be elucidated. In the present study, we sought to determine the type of CD4+ lymphocytes recruited to the liver after ischemia-reperfusion and the manner in which these cells regulated neutrophil recruitment and tissue injury. Wild-type and CD4 knockout (CD4−/−) mice were subjected to hepatic ischemia-reperfusion. CD4+ lymphocytes were recruited in the liver within 1 h of reperfusion and remained for at least 4 h. These cells were comprised of conventional (αβTCR-expressing), unconventional (γδTCR-expressing), and natural killer T cells. CD4−/− mice were then used to determine the functional role of CD4+ lymphocytes in hepatic ischemia-reperfusion injury. Compared with wild-type mice, CD4−/− mice had significantly greater liver injury, yet far less neutrophil accumulation. Adoptive transfer of CD4+ lymphocytes to CD4−/− mice recapitulated the wild-type response. In wild-type mice, neutralization of interleukin (IL)-17, a cytokine released by activated CD4+ lymphocytes, significantly reduced neutrophil recruitment in association with suppression of MIP-2 expression. Finally, oxidative burst activity of liver-recruited neutrophils was higher in CD4−/− mice compared with those from wild-type mice. These data suggest that CD4+ lymphocytes are rapidly recruited to the liver after ischemia-reperfusion and facilitate subsequent neutrophil recruitment via an IL-17-dependent mechanism. However, these cells also appear to attenuate neutrophil activation. Thus the data suggest that CD4+ lymphocytes have dual, opposing roles in the hepatic inflammatory response to ischemia-reperfusion.

scholarly journals PKCβ modulates ischemia-reperfusion injury in the heart

2008 ◽  
Vol 294 (4) ◽  
pp. H1862-H1870 ◽  
Author(s):  
Linghua Kong ◽  
Martin Andrassy ◽  
Jong Sun Chang ◽  
Chun Huang ◽  
Tomohiro Asai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Enhanced Recovery ◽  
Ischemia Reperfusion ◽  
Homozygous Deletion ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Lv Function ◽  
Wild Type

Protein kinase C-βII (PKCβII) is an important modulator of cellular stress responses. To test the hypothesis that PKCβII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCβ-null (PKCβ−/−) and wild-type mice fed the PKCβ inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCβII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCβ protected ischemic myocardium. Homozygous deletion of PKCβ significantly diminished phosphorylation of c-Jun NH2-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCβ in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCβ may represent a potent strategy to protect the vulnerable myocardium.

scholarly journals Reduced mitochondrial Ca2+ loading and improved functional recovery after ischemia-reperfusion injury in old vs. young guinea pig hearts

2012 ◽  
Vol 302 (3) ◽  
pp. H855-H863 ◽  
Author(s):  
Samhita S. Rhodes ◽  
Amadou K. S. Camara ◽  
James S. Heisner ◽  
Matthias L. Riess ◽  
Mohammed Aldakkak ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Guinea Pigs ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Ringer Solution ◽  
Left Ventricular ◽  
Fiber Optic Probe ◽  
Optic Probe ◽  
Inotropic Responses

Oxidative damage and impaired cytosolic Ca2+ concentration ([Ca2+]cyto) handling are associated with mitochondrial [Ca2+] ([Ca2+]mito) overload and depressed functional recovery after cardiac ischemia-reperfusion (I/R) injury. We hypothesized that hearts from old guinea pigs would demonstrate impaired [Ca2+]mito handling, poor functional recovery, and a more oxidized state after I/R injury compared with hearts from young guinea pigs. Hearts from young (∼4 wk) and old (>52 wk) guinea pigs were isolated and perfused with Krebs-Ringer solution (2.1 mM Ca2+ concentration at 37°C). Left ventricular pressure (LVP, mmHg) was measured with a balloon, and NADH, [Ca2+]mito (nM), and [Ca2+]cyto (nM) were measured by fluorescence with a fiber optic probe placed against the left ventricular free wall. After baseline (BL) measurements, hearts were subjected to 30 min global ischemia and 120 min reperfusion (REP). In old vs. young hearts we found: 1) percent infarct size was lower (27 ± 9 vs. 57 ± 2); 2) developed LVP (systolic-diastolic) was higher at 10 min (57 ± 11 vs. 29 ± 2) and 60 min (55 ± 10 vs. 32 ± 2) REP; 3) diastolic LVP was lower at 10 and 60 min REP (6 ± 3 vs. 29 ± 4 and 3 ± 3 vs. 21 ± 4 mmHg); 4) mean [Ca2+]cyto was higher during ischemia (837 ± 39 vs. 541 ± 39), but [Ca2+]mito was lower (545 ± 62 vs. 975 ± 38); 5) [Ca2+]mito was lower at 10 and 60 min REP (129 ± 2 vs. 293 ± 23 and 122 ± 2 vs. 234 ± 15); 6) reduced inotropic responses to dopamine and digoxin; and 7) NADH was elevated during ischemia in both groups and lower than BL during REP. Contrary to our stated hypotheses, old hearts showed reduced [Ca2+]mito, decreased infarction, and improved basal mechanical function after I/R injury compared with young hearts; no differences were noted in redox state due to age. In this model, aging-associated protection may be linked to limited [Ca2+]mito loading after I/R injury despite higher [Ca2+]cyto load during ischemia in old vs. young hearts.

Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury

2015 ◽  
Vol 308 (8) ◽  
pp. H894-H903 ◽  
Author(s):  
Ken Shinmura ◽  
Kayoko Tamaki ◽  
Kentaro Ito ◽  
Xiaoxiang Yan ◽  
Tsunehisa Yamamoto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Sirtuin 1 ◽  
Wild Type ◽  
Endothelial Nitric Oxide

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with NG-nitro-l-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS−/−) mice to either 3-mo ad libitum (AL) feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS−/− mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS−/− mice. eNOS−/− mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS−/− mice. In eNOS−/− mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS−/− mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS−/− mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.

Sign in / Sign up

Export Citation Format

Share Document