The Role of SIRT4 in Myocardial Ischemia Reperfusion Injury

• Applicant: Professor Dr. Heiko Bugger
• Subject Area: Cardiology, Angiology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289747768

Cellular damage after reperfusion of previously viable ischemic myocardium is defined as myocardial ischemia reperfusion (IR) injury and contributes to myocardial infarct size. Structural and functional alterations in mitochondria contribute to the extent of myocardial IR injury, in particular opening of the mitochondrial permeability transition pore (mPTP), which leads to mitochondrial swelling, membrane rupture and ultimately cell death. Recent evidence suggests a regulation of mPTP opening by the mitochondrial NAD+-dependent enzyme sirtuin 4 (SIRT4), down-regulation of which increased resistance to mPTP induction in cultured cells. Preliminary studies in our laboratory revealed a 50% reduction in myocardial infarct size following transient ligation of the left anterior descending coronary artery in SIRT4-/- mice. Similarly, post-ischemic recovery of contractile function was improved during reperfusion in isolated perfused SIRT4-/- hearts, accompanied by a decrease in Ca2+-induced mitochondrial swelling suggestive of decreased sensitivity for mPTP opening. Since these results suggest that suppression of SIRT4 may be a cardioprotective mechanism in IR, we propose (1) to investigate the effect of modulating SIRT4 levels on myocardial IR injury, and (2) to elucidate the mechanism of cardioprotection in mice lacking SIRT4. The resulting data will increase our understanding of myocardial IR injury and may provide a novel target for cardioprotection.

• DFG Programme: Research Grants