Roles for SGK1 in Cardiometabolic Heart Failure with Preserved Ejection Fraction - Project Summary: Heart failure with preserved ejection fraction (HFpEF) has emerged as the greatest unmet medical need in cardiovascular medicine, comprising 50% of all HF cases, with a US prevalence of ³3 million. HFpEF is associated with high morbidity and mortality, with a 5-year survival after hospitalization worse than most cancers of ~35% and, unlike the better understood heart failure with reduced ejected fraction (HFrEF), there are no evidence-based therapies for HFpEF. HFpEF represents an entirely new disease threat because of the systemic metabolic and endocrine nature of its pathogenesis. And, while HFpEF is heterogeneous in its clinical presentation, arguably the most prevalent form is cardiometabolic HFpEF (cMet HFpEF), where the main comorbidities are obesity, type 2 diabetes, and hypertension. These same comorbidities are the major drivers of concomitant obesity-related diseases that includes nonalcoholic fatty liver disease (NAFLD), which is prevalent in more than 50% of HFpEF patients and has been demonstrated to be an independent predictor of all-cause mortality in HFpEF. This is of unique concern as the obesity epidemic continues to grow with current estimations that 45% of the world’s population is either overweight or obese. Our preliminary data support the notion that the heart is a primary regulator of global metabolic syndrome through the serine-threonine kinase, serum glucocorticoid kinase 1 (SGK1). Global SGK1 overexpression has been demonstrated to promote increased obesity, dyslipidemia, while liver-specific deletion of SGK1 has been shown to protect against NAFLD. While there is a clear connection between SGK1 and obesity-related metabolic syndrome, neither a role for SGK1 in cMet HFpEF nor the mechanism by which SGK1 regulates cellular metabolism have been investigated. In this proposal, we will focus on cardiac-specific SGK1 in cMet HFpEF with the hypothesis that SGK1 promotes increased mTORC1 activity in the heart via phosphorylating PRAS40 which exacerbates cardiac pathology and subsequent global metabolic dysfunction in cMet HFpEF. We will address this hypothesis using cardiac-specific targeting of SGK1 and PRAS40 in a mouse model of cMet HFpEF with a focus on assessments of cardiac function and metabolism, as well as mechanistic studies in primary cardiomyocytes, in the following Specific Aims which are to: (Aim 1) determine the role for cardiac SGK1-PRAS40 signaling in regulating heart function, metabolism, and heart directed inter-organ communication during cMet HFpEF, (Aim 2) determine whether PRAS40 inhibition by SGK1 promotes mTORC1 mediated pathologic cardiac metabolic inflexibility during cMet HFpEF, and (Aim 3) evaluate the therapeutic efficacy of a novel SGK1 inhibitory peptide for preserving cardiac function and systemic metabolism during cMet HFpEF. These studies are significant as the present the opportunity to identify novel secreted factors from the heart that regulate global metabolic health as well as to test new therapeutic targets for both HFpEF and obesity-related diseases.
