Abstract MP23: Vascular Smooth Muscle Rho-related Btb Domain Containing Protein 1 In Hypertension And Arterial Stiffness

Abstract

Rho-related BTB domain containing protein 1 (RhoBTB1) is a transcriptional target of peroxisome proliferator activated receptor γ (PPARγ), but its physiological and molecular function in blood pressure (BP) control remains unclear. We showed that aortic RhoBTB1 expression was decreased in mice expressing vascular smooth muscle (VSM) specific dominant negative PPARγ mutation (S-P467L). Genetic complementation of VSM RhoBTB1 reversed the hypertension, vascular dysfunction, and arterial stiffness in S-P467L mice; and suppressed the elevated enzymatic activity of phosphodiesterase 5 (PDE5) in S-P467L mice. In HEK293 cells, RhoBTB1 increases PDE5 ubiquitination in a Cullin-3-dependent manner. We concluded that VSMC RhoBTB1 mediates the anti-hypertensive effect of PPARγ. RhoBTB1 expression was decreased in aorta from mice treated with angiotensin II (AngII, 490ng/kg/min, 2-weeks). We hypothesized that restoration of VSM RhoBTB1 would reverse established AngII-mediated hypertension, vascular dysfunction, and arterial stiffness. Transgenic mice expressing inducible VSM-specific RhoBTB1 (S-RhoBTB1) were treated with AngII (490ng/kg/min, 6-weeks) and the transgene was activated by Tamoxifen (Tx) during week 3. ISM-Cre mice expressing VSM Cre-recombinase were similarly treated as controls. AngII equally increased BP, as measured by radiotelemetry in both ISM-Cre and S-RhoBTB1 mice. The vasodilatory and vasoconstrictor responses in the carotid artery were not different in AngII-treated S-RhoBTB1 and ISM-Cre mice. RhoBTB1 did not affect pulse wave velocity (PWV), a measure of arterial stiffness, in mice without AngII (ISM-Cre vs S-RhoBTB1: 2.64±0.08 vs 2.48±0.06 mm/ms, p>0.05, n=6); and AngII increased PWV similarly in both strains before Tx (ISM-Cre vs S-RhoBTB1: 3.54±0.22 vs 3.52±0.18 mm/ms, p>0.05, n=7-9). PWV of S-RhoBTB1 mice started to decrease after the first week whereas it continued to rise in ISM-Cre mice. By the second week of Tx, VSMC RhoBTB1 expression significantly attenuated AngII induced arterial stiffness (ISM-Cre vs S-RhoBTB1: 4.21±0.37 vs 3.17±0.16 mm/ms, p=0.02, n=7-9). These data suggest a mechanism where RhoBTB1 improves vascular compliance independently from BP and is protective against arterial stiffness.