Sirtuins are NAD-dependent deacetylases that remove a broad variety of different posttranslational modifications from protein lysine residues, thereby regulating protein function. In mammals, seven sirtuins (SIRT1-7) have been identified, which are localized in the cytosol (SIRT1, SIRT2, SIRT6), in the nucleus (SIRT1, SIRT6, SIRT7), or primarily within mitochondria (SIRT3, SIRT4, SIRT5). Sirtuins regulate a large variety of biological functions, including regulation of glucose and lipid metabolism, detoxification of ROS, control of mitochondrial biogenesis and dynamics, regulation of gene transcription, mechanisms underlying increased longevity, and adaptive mechanisms conferring stress resistance. Sirtuins are important sensors of energy status that can adapt ATP synthesis to cellular energy demand, and that counteract cellular stress and are thus thought to serve as redox-sensitive stress adaptors, e.g. to genotoxic or hypoxic stress.

Sirtuins are abundantly expressed in the heart, and impaired activity of sirtuins within cardiomyocytes has been implied in the development of various cardiac diseases, including diabetic cardiomyopathy, heart failure, and myocardial ischemia reperfusion injury, among others. Inflammation and responses of inborn and adaptive immunity also participate in the pathogenesis of heart failure and in the cardiac healing and remodeling process following myocardial ischemia reperfusion. Infiltration of macrophages or T cells, activation of intracellular signaling cascades (e.g. NLRP3 inflammasome activation), and release of pro-inflammatory cytokines by specific immune cell subsets are mechanisms that may contribute to cardiac disease pathologies such as structural remodeling, fibrosis, or oxidative stress. Of note, sirtuins also regulate metabolism and redox status in immune cells, thereby modulating proliferation, differentiation and effector functions of immune cells and thus shaping immune responses.

Our research aims to understand the role and mechanisms of mitochondrial sirtuins in the pathogenesis of myocardial ischemia reperfusion injury and heart failure at the interface of metabolism and immunity, in particular in the setting of systemic metabolic stress as occurs in obesity and type 2 diabetes mellitus.