Abstract 068: Role for the Rho-GAP Graf3 in the Pathogenesis of Human Hypertension [Session Title: Concurrent XIV B: Vascular Biology I]

Activation of RhoA in vascular smooth muscle cells (SMC) has been linked to vasoconstrictor-induced hypertension (HTN), but the relevance of this pathway to human disease was undetermined. We identified GRAF3 as a RhoA-GAP expressed specifically in SMC in mice and humans and reported that global GRAF3-deficient mice exhibited significant basal HTN (+ 25 mm Hg) that was fully reversed by treatment with a Rho-kinase inhibitor (Nature Comm. 2013;4:2910). Importantly, we recently created a tamoxifen inducible SMC-GRAF3 re-expression model which resulted in a near complete reversal of MAP (from 123 mmHg to 95 mm Hg), indicating that GRAF3's ability to limit RhoA activity in SMC is required for the maintenance of normal BP. Given that a BP-associated locus within the GRAF3 gene was identified by Genome Wide Association, we next sought to characterize the mechanisms that control GRAF3 expression. Through the use of a series of siRNA-dependent approaches in cultured SMC, we found that SMC-specific expression of GRAF3 is mediated by the RhoA/MRTF-A/SRF-signaling axis. Interestingly, RhoA is known to be activated by mechanical forces and we found that GRAF3 expression was significantly increased (8-fold) in vessels subjected to pathological stress. The finding that GRAF3 expression was significantly increased in two separate hypertensive animal models relative to their littermate controls provides further evidence that GRAF3 expression is regulated as part of an auto-regulatory negativ...
Source: Hypertension - Category: Cardiology Authors: Tags: Session Title: Concurrent XIV B: Vascular Biology I Source Type: research