Vascular Pyruvate Kinase M2 in Hypertension

University Of South Florida, Tampa FL

Investigators

Abstract

Hypertension is the most significant health burden for society in terms of economic and health costs due to the increased risk for cardiovascular disease (CVD) such as myocardial infarction and stroke. Patients with hypertension have significantly greater risks for cardiovascular mortality and morbidity compared to age matched normotensive subjects, even when the patient’s blood pressure is controlled with medication. Therefore, the long-term goal of our application is to investigate the core mechanism of vascular remodeling associated with hypertension so that an effective add-on therapy can be explored for patients with hypertension. Metabolic shift to glycolysis has been recognized in many types of CVD including hypertension. However, limited information is available regarding the types of cells influenced, if it contributes to hypertension or remodeling, as well as critical mechanisms involved. The renin-angiotensin system is considered to play a central role in hypertension as well as the associated tissue/cell phenotypes including ER stress. While the RAS affects a variety of cells and hypertension demonstrates a complex pathophysiology, our preliminary data with vascular smooth muscle cell (VSMC) AT1a receptor deficient mice have demonstrated a critical role of VSMC signaling in angiotensin II (AngII)-dependent vascular remodeling. Accordingly, in this application, we will explore the essential glycolytic enzyme pyruvate kinase M2 (PKM2) activation in VSMC via AngII that uniquely mediates vascular remodeling and hypertension involving alterations in conductance as well as resistance arteries. Based on promising preliminary data, we propose a central hypothesis that the VSMC PKM2 mediates hypertension and vascular remodeling in conductance and resistance arteries, which likely involves both metabolic and non-metabolic effects via its pyruvate kinase and specific protein kinase activities. Three specific Aims are proposed to explore the vascular mechanisms and the relevance of their signal communication utilizing two distinct models of hypertension as well as aortic VSMC and fibroblasts in vitro. Aim 1 will study involvement of PKM2 activation in VSMC in hypertension and vascular remodeling. Aim 2 will study novel mechanisms of how PKM2 activation in VSMC, glycolysis dependently and independently, mediates hypertension and vascular remodeling. Aim 3 will explore VSMC-to-fibroblast communication in hypertensive vascular fibrosis via VSMC PKM2 mediated secretome as well as lactate shuttle. To study the cell type and mechanism by which PKM2 is involved in hypertension and hypertensive vascular remodeling, we will utilize genetically or pharmacologically altered mice infused with AngII. In addition, to enhance translational relevance we will utilize spontaneously hypertensive rats (SHR) as a model for human essential hypertension with pharmacological manipulations against PKM2. Accomplishment of the proposal will yield significant advancement of our knowledge regarding the mechanisms leading to the development of hypertensive vascular remodeling and provide future translational research leading to new therapies.