Abstract
Anti-hypertensive therapies are usually prescribed empirically and are often ineffective. Given the prevalence and deleterious outcomes of hypertension (HTN), improved strategies are needed. We reported that the Rho-GAP GRAF3 is selectively expressed in smooth muscle cells (SMC) and controls blood pressure (BP) by limiting the RhoA-dependent contractility of resistance arterioles. Importantly, genetic variants at the GRAF3 locus controls BP in patients. The goal of this study was to validate GRAF3 as a druggable candidate for future anti-HTN therapies. Importantly, using a novel mouse model, we found that modest induction of GRAF3 in SMC significantly decreased basal and vasoconstrictor-induced BP. Moreover, we found that GRAF3 protein toggles between inactive and active states by processes controlled by the mechano-sensing kinase, focal adhesion kinase (FAK). Using resonance energy transfer methods, we showed that agonist-induced FAK-dependent phosphorylation at Y376GRAF3 reverses an auto-inhibitory interaction between the GAP and BAR-PH domains. Y376 is located in a linker between the PH and GAP domains and is invariant in GRAF3 homologues and a phosphomimetic E376GRAF3 variant exhibited elevated GAP activity. Collectively, these data provide strong support for the future identification of allosteric activators of GRAF3 for targeted anti-hypertensive therapies.
Highlights
High blood pressure, known clinically as hypertension (HTN), is a highly prevalent and relevant disease in the Western world and is a major risk factor for myocardial infarction, stroke, and kidney failure
Vascular resistance is a major determinant of blood pressure (BP) and is controlled, in large part, by RhoA-dependent smooth muscle cell (SMC) contraction within small peripheral arterioles [5,6,7,8,45]
Previous studies from our lab indicate that GRAF3 limits RhoA activity in vascular smooth muscle cells (SMC) and endogenous GRAF3 controls SMC tone by reducing SMC calcium sensitivity and restraining expression of the SMC-specific contractile proteins that support this function [18,19,46]
Summary
Known clinically as hypertension (HTN), is a highly prevalent and relevant disease in the Western world and is a major risk factor for myocardial infarction, stroke, and kidney failure. It is estimated that 1 in every 3 adults in the US has HTN and another 1 in 3 has prehypertension [1]. It is estimated that only half of medicated adults have their blood pressure (BP) under control [4]. Given the prevalence of HTN and its deleterious effects on cardiovascular outcomes, the identification of better HTN therapies could lead to a huge reduction in global cardiovascular disease burden. While BP regulation involves the integrated control of many different organ systems and the interplay of many genes [5,6], one of the key components of HTN is increased peripheral vascular resistance due to the contraction of vascular smooth muscle within the arteriole wall [5,6,7,8]
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