Abstract 062: Vascular Dysfunction and Hypertension are Prevented by a Novel PPARγ Target Gene, RhoBTB1

Abstract

RhoBTB1 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) target gene expressed in smooth muscle cells (SMC) which may mediate some of the vascular protective and antihypertensive benefits of PPARγ. Here, we tested the hypothesis that RhoBTB1 can prevent angiotensin II (ANG)-induced hypertension. RhoBTB1 expression in aorta from C57BL/6 mice was decreased by 54±9% (n=16) in response to ANG infusion (490 ng/min/kg, 2 weeks). To test if RhoBTB1 expression is protective, we generated double transgenic mice with tamoxifen-inducible, Cre-dependent overexpression of RhoBTB1 specifically in SMC (S-RhoBTB1). S-RhoBTB1 and non-transgenic (NT) mice were treated with tamoxifen (Tx; 75 mg/kg, ip, 5 days) or vehicle (corn oil) and then ANG was infused. Although RhoBTB1 expression was decreased in ANG-infused control mice (p<0.01, n=8-10), RhoBTB1 expression in Tx-treated S-RhoBTB1 mice infused with ANG was restored to a level similar to NT treated with saline (n=11). Overexpression of RhoBTB1 did not alter baseline blood pressure (BP) in the absence of ANG (n=7-8). However, the increase in BP induced by ANG was significantly attenuated by RhoBTB1 restoration in S-RhoBTB1 mice with Tx compared to ANG-infused control mice (either NT with Tx, NT with corn oil, or S-RhoBTB1 with corn oil) in which RhoBTB1 was not restored (Systolic BP, 159±5 in control mice vs 132±6 mmHg in S-RhoBTB1 mice with Tx, p<0.01, n=7-8). We also observed increased heart weight in ANG-infused control mice, which was prevented in S-RhoBTB1 mice treated with Tx (p<0.05, n=8). Thoracic aorta and basilar artery from ANG-infused control mice exhibited impaired acetylcholine-induced endothelial-dependent relaxation (Aorta, 48±2%, p<0.01, n=6-8), which was prevented by restoration of RhoBTB1 in SMC (Aorta, 76±5%, p<0.01, n=6-8). Thoracic aorta from ANG-infused control mice also displayed decreased sodium nitroprusside-induced endothelial-independent relaxation with a right-shifted dose-response (76±9%, p<0.01, n=8), which was also prevented in tamoxifen-treated S-RhoBTB1 mice (95±10%, p<0.01, n=8). We conclude that the novel PPARγ target gene, RhoBTB1, functions in SMC to specifically facilitate vasodilation and mediates a protective anti-hypertensive effect.