Targeting salt-inducible kinases to improve the cardiometabolic fitness in HFpEF

Diabetes and obesity negatively impact cardiovascular function and are closely associated with heart failure with preserved ejection fraction (HFpEF), a prevailing condition that accounts for half of HF cases. Evidence from both patients and rodent models suggested that obesity-induced metabolic dysfunction is a critical driver in HFpEF. As a metabolically active organ, the failing heart demonstrates fuel deficits primarily due to mitochondrial dysfunction that reduces high-capacity oxidative metabolism. Druggable targets for reversing this metabolic defect in HFpEF are lacking. Salt-inducible kinases (SIKs) are critical regulators of cardiometabolic disease. Our recent publication showed that pharmacological SIK inhibition promotes the adipocyte thermogenic and mitochondrial biogenesis gene program and adipose tissue browning. In this proposal, we reason that targeting SIKs to treat obesity-related metabolic dysfunction would be beneficial for HFpEF. In support of this notion, our preliminary study shows that SIK inhibition limits adiposity, enhances glucose homeostasis, and improves the cardiac diastolic function in a preclinical mouse model of HFpEF. Furthermore, we found that a common SIK3 variant rs12225230, encoding a Proline1136 to Arginine (P1136R) missense mutation, impairs SIK3 function and is associated with a protective effect against diabetes and cardiovascular disease. The objective of this proposal is to probe the pathological role of SIKs in obesity and HFpEF. Our central hypothesis is that SIKs restrict energy metabolism and cardiovascular function under cardiometabolic stress, and that SIK inhibition will protect against obesity-related complications and improve the cardiometabolic outcomes in HFpEF. We further hypothesize that P1136R mutation impairs SIK3 action and enhances insulin and mitochondrial function in the adipocyte and cardiomyocyte to confer a cardiometabolic protective effect. We will test these hypotheses with two specific aims. Aim 1 will be to test whether oral SIK inhibitor treatment improves energy metabolism and cardiac function in HFpEF. We will use comprehensive cardiometabolic, histological and molecular approaches to investigate the treatment effects of two recently developed oral SIK inhibitors in HFpEF mouse model. Aim 2 will be to test whether the P1136R mutation alters SIK3 action and improves insulin and mitochondrial function in the adipocyte and cardiomyocyte. We will utilize biochemical assays and primary cell models to characterize the function of P1136R mutation to determine its impact on SIK3 kinase activity, substrate regulation, and insulin and mitochondria function. This proposal is innovative because it uses SIK inhibitors as an interventional and potentially translatable approach to probe the role of SIKs in HFpEF pathophysiology. It will provide new insights into whether a common SIK3 gene polymorphism could lead to a cardiometabolic protection effect. Funding for this proposal will allow us to generate additional preliminary data and necessary reagents that will make it possible to submit a R01 application. It will also boost the broader impact of the DRTC P&F program in the cardiometabolic disease research community.