Abstract
Introduction: A “longevity” gene, sirtuin 1 (SIRT1) is a conserved NAD + -dependent protein deacetylase that regulates life span extension. We have reported that SIRT1 is down-regulated in the aged heart which shows larger infarct size and deteriorative heart function during ischemia and reperfusion (I/R) compared with that of young heart. Hypothesis: Cardiac specific SIRT1 deficiency could increase the sensitivity of heart to ischemic insults caused by ischemia and reperfusion. Methods: Male SIRT1 flox/flox mice and tamoxifen-inducible, cardiac-specific SIRT1 KO mice were subjected to I/R, which were induced by occluding the left anterior descending coronary (LAD) and subsequent releasing it. Langendorff-perfused heart model was used to monitor the heart function during I/R. Results: Adult cardiac-specific SIRT1 KO demonstrated significant cardiac hypertrophy, fibrosis and macrophage infiltration under normal physiological conditions versus the SIRT1 flox/flox hearts by immunohistochemical staining (all p<0.05). The cardiac functions measured by the pressure-volume loop remained normal in SIRT1 KO mice as compared with SIRT1 flox/flox mice under physiological conditions. The ex vivo heart perfusion results showed that the heart rate-left ventricular developed pressure product in SIRT1 KO hearts was decreased by 30% versus the SIRT1 flox/flox hearts (p<0.05), and the infarct size of SIRT1 KO hearts was 1.7-fold larger than that of SIRT1 flox/flox hearts (p<0.05). The immunoblotting data demonstrated that SIRT1 KO hearts had impaired responsive activation of AMP-activated protein kinase (AMPK) signaling during I/R versus the SIRT1 flox/flox hearts. Furthermore, real-time qRT-PCR showed that cardiac SIRT1 KO resulted in up-regulation of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin-1 β and growth differentiation factor15 (GDF15), as well as a heart failure marker ANP (atrial natriuretic peptide) versus SIRT1 flox/flox hearts during I/R. Conclusions: SIRT1 plays a vital role in regulation of myocardial infarction, heart function and inflammation induced by I/R in the heart. SIRT1 specific agonists may have therapeutic potential for treatment of ischemic heart disease.
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