Protective Role of Vascular Smooth Muscle RhoBTB1 in Hypertension

Abstract

RhoBTB1 is an atypical GTPase, which is associated with human hypertension according to a genome‐wide association study. However, the physiological and molecular role of RhoBTB1 is not well understood. Previously, we showed that aortic RhoBTB1 is downregulated in two hypertension models including systemic angiotensin II (Ang II) infusion and vascular smooth muscle (VSM) specific expression of human hypertension causing dominant negative PPAR gamma mutant P467L (S‐P467L). To achieve RhoBTB1 genetic complementation, we generated mice with VSM specific, tamoxifen inducible RhoBTB1 (S‐RhoBTB1) expression. Previous studies showed that S‐RhoBTB1 mice are resistant to Ang II‐induced hypertension. In the current study, we are investigating whether restoration of RhoBTB1 expression is sufficient to reverse established Ang II‐induced hypertension. S‐RhoBTB1 mice received systemic Ang II‐infusion (490ng/kg/min) for two weeks before tamoxifen injection. However, S‐RhoBTB1 did not reverse Ang II‐induced elevated blood pressure. Aorta and carotid artery still exhibited impaired vasodilation to acetylcholine and sodium nitroprusside. Pulse wave velocity was elevated in both S‐RhoBTB1 and non‐transgenic mice receiving Ang II infusion, indicating a persistence of arterial stiffness. Unlike Ang II infusion, restoration of RhoBTB1 was sufficient to reverse hypertension, vascular dysfunction and arterial stiffness in S‐P467L mice. In S‐P467L mice aorta, the activity of phosphodiesterase 5 (PDE5), an enzyme that degrades vasodilator cGMP, was elevated in S‐P467L and normalized upon RhoBTB1 restoration. We transfected HEK293 cells with RhoBTB1 and PDE5 and found, using co‐immunoprecipitation, that PDE5 physically interacts with RhoBTB1. Moreover, RhoBTB1 increased PDE5 ubiquitination in a Cullin3‐dependent manner. Hence, a potential molecular mechanism underlying RhoBTB1's cardiovascular protective role is that RhoBTB1 acts as a substrate adaptor for Cullin3‐RING dependent ubiquitin ligase. In conclusion, RhoBTB1 might be a novel hypertension therapeutic target, which requires further characterization.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.