A Stress Inducible Protein Sestrin2 in Heart Failure

Heart failure is an increasingly prevalent problem and particularly so amongst an aging Veterans population. From a clinical standpoint, the prevalence of comorbid conditions such as obesity, diabetes, COPD (chronic obstructive pulmonary disease), aging and hypertension in these patients has led to the inflammatory hypothesis where heart failure is also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of maladaptive substrate metabolism and impaired coronary flow regulation in the development of the heart failure remain unclear. The work described in this proposal combines experiments at the basic and translational research level to address the critical need of our veterans for novel and effective heart failure therapies. The long-term goal of our research is to understand the molecular mechanisms that underlie the role of Sestrin2 (Sesn2), a stress inducible protein, in mediating progression from compensated left ventricular hypertrophy to decompensated hypertrophy and maladaptive ventricular remodeling in heart failure. We have demonstrated that Sesn2 is a mediator of physiologic and pathologic cardiac hypertrophy and are now seeking to define the underlying molecular mechanisms. Sesn2 knockout (Sesn2 KO) mice display normal cardiac function at rest compared to wild type (WT) littermates but are vulnerable with pathologic hypertrophy in response to pressure overload. Furthermore, recently published data from our lab show that Sesn2 serves as an age- related protein that modulates AMPK, a cardiac energy sensor, to maintain metabolic homeostasis under stress conditions. Aging related heart failure could be due to impaired Sesn2-AMPK signaling cascade occurring in synergy with the adverse effects of hypertension. Thus, our central hypothesis is that Sesn2 serves as a scaffold protein that plays a key role in hypertension induced heart failure in aging. Aim 1: To determine the upstream signaling pathways that control cardiac Sesn2 expression, and the mechanisms by which Sesn2-mediated AMPK signaling inhibits development of hypertension-induced heart failure in aging. Aim 2: To determine the role of Sesn2-mTORC1 complex in the cardiac response to hypertension and aging. Our long-term objective is to improve the care of Veterans with heart failure by developing a better understanding of the mechanisms leading to heart failure and identifying novel targeted treatments that can prevent or reverse hypertensive heart failure.