P5381Lack of sirtuin 5 aggravates myocardial ischemia reperfusion injury

Abstract

Abstract Sirtuin 5 (SIRT5) is a mitochondrial NAD+-dependent protein deacylase which regulates the enzymatic activity of numerous mitochondrial proteins due to increased succinylation and malonylation, including enzymes of energy substrate oxidation and mitochondrial antioxidant enzymes. Since energy depletion and mitochondrial oxidative stress contribute to myocardial IR injury, it was our objective to evaluate the potential role of SIRT5 in IR injury. In regular Langendorff heart perfusions, 8 week-old cardiomyocyte-selective SIRT5−/− mice showed no difference in LV developed pressure or dp/dt max compared to wildtype mice. However, recovery of LV developed pressure and dp/dt max following 25 min of ischemia was lower by 34% and 20% in SIRT5−/− mice compared to WT mice, respectively. In contrast, postischemic recovery of cardiac function was not impaired and even improved in mice with cardiomyocyte-selective overexpression of SIRT5 compared to WT mice undergoing IR. Mitochondrial H2O2 generation was significantly increased in SIRT5−/− mice compared to WT mice following IR, and mitochondria-targeted antioxidant treatments (MnTBAP or SS-31) during heart perfusion completely normalized recovery of contractile parameters in SIRT5−/− mice following IR. In conclusion, SIRT5 is not required to maintain cardiac function under physiological conditions. However, lack of SIRT5 aggravates myocardial IR injury, likely by increasing mitochondrial oxidative stress. SIRT5 agonism may thus represent a potential therapeutic strategy to attenuate myocardial IR injury.