Sirtuin 4 and Reactive Oxygen Species in Cardioprotection

Myocardial infarction is a frequent cause of death, often caused by the acute occlusion of a coronary artery. If blood flow is not restored within a short time frame, the lack of blood flow (i.e. ischemia) will result in cardiomyocyte death. The longer the ischemic time, the larger the size of the myocardial infarct. Treatment of choice for patients with acute myocardial infarction is therefore to immediately restore myocardial blood flow by reopening the occluded vessel. However, a significant extent of myocardial injury also occurs following restoration of blood flow, an injury termed reperfusion injury. To date, no treatment is available in clinical practice to reduce myocardial reperfusion injury. Mitochondria are cell organelles that regenerate ATP and thus are the powerhouse of cells. Impairment of mitochondrial function is a central mechanism contributing both to ischemic and reperfusion injury, both due to energy depletion and by increasing oxidative damage to mitochondrial structures. Sirtuins are a family of proteins that remove protein modifications from other proteins, thereby regulating their function. Activation of sirtuins protects from a variety of age-related diseases. We recently observed that modulation of sirtuin activity determines cardiac infarct size. This protective effect may result from suppression of mitochondrial oxidative stress, resulting either from beneficial effects of sirtuins on mitochondrial energy metabolism, or from increased expression of enzymes that detoxify mitochondrial reactive oxygen species. The aim of this project is to identify the metabolic and transcriptional mechanisms by which specific mitochondrial sirtuins limit mitochondrial oxidative stress and confer cardioprotection during myocardial ischemia and reperfusion. The study will increase our understanding how sirtuins may regulate energy metabolism, reactive oxygen species, and gene transcription, both under physiologic conditions and during myocardial infarction. The results may further support the rising concept that maintaining mitochondrial sirtuin activity during myocardial ischemia and reperfusion may represent a promising therapeutic approach to attenuate cardiac damage in patients suffering myocardial infarction.

Myocardial infarction is a frequent cause of death, often caused by the acute occlusion of a coronary artery. If blood flow is not restored within a short time frame, the lack of blood flow (i.e. ischemia) will result in cardiomyocyte death and ultimately heart failure. Treatment of choice for patients with acute myocardial infarction is therefore to immediately restore myocardial blood flow by reopening the occluded vessel by coronary intervention in the cardiac catheterization laboratory. However, a significant extent of myocardial injury also occurs following restoration of blood flow, an injury termed reperfusion injury. To date, no treatment is available in clinical practice to reduce myocardial reperfusion injury. Mitochondria are cell organelles that regenerate high energy phosphates and thus are the powerhouse of cells. Impairment of mitochondrial function is a central mechanism contributing both to ischemic and reperfusion injury, both due to energy depletion and by increasing oxidative damage to mitochondrial structures. Sirtuin 4 (SIRT4) is a protein that removes modifications from target proteins to regulate essential cellular processes such as reactive oxygen species homeostasis and cellular metabolism. In this project, we found that suppression of SIRT4 decreases myocardial infarct size and attenuates ischemia reperfusion injury, likely due to a suppression of oxidative stress within mitochondria. We performed in-depth analysis using an isotope tracer study to identify the metabolic alterations by which suppression of SIRT4 may attenuate ischemia reperfusion injury, and preliminary analyses identified significant alterations in mitochondrial energy metabolism by which SIRT4 may mediate oxidative stress in mitochondria. In addition, we identified up to 16 novel SIRT4 targets which may be involved in mediating the protective effect on infarct size under conditions of SIRT4 suppression, including the known oxygen radical producing enzyme, NOX4. Furthermore, we found that the development of heart failure, a longterm outcome of myocardial infarction, is accelerated by SIRT4-mediated oxidative stress. Collectively, our studies suggest that SIRT4 is a central regulator of mitochondrial reactive oxygen species homeostasis and metabolism in the heart, suppression of which may mediate beneficial effects both in the acute setting of myocardial infarction but also during longterm heart failure development. Ongoing studies to further understand the mechanistic underlying mechanisms of SIRT4 action and SIRT4 suppression may help to support the concept that SIRT4 suppression may represent a promising therapeutic approach to attenuate cardiac damage in patients suffering myocardial infarction and subsequent heart failure.