Abstract 529: Atorvastatin and Sildenafil Reduce Vascular Remodeling and Oxidative Stress in 2K1C-hypertension

Abstract

Atorvastatin (ATORVA) and sildenafil (SILD) exert beneficial effects on cardiovascular diseases through their pleiotropic effects. Hypertension-induced vascular hypertrophy is associated with oxidative stress and matrix metalloproteinase (MMP) up-regulation. We evaluated the effects of ATORVA and SILD on vascular changes induced by MMPs and on oxidative stress and MMP activity in 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were treated with vehicle, ATORVA (50 mg/kg), SILD (45 mg/kg) or both for 8 weeks. ATORVA, SILD, or both drugs exerted antihypertensive effects (systolic blood pressure: 148±6, 156±2, and 138±4 mmHg, respectively, vs. 200±4 mmHg in 2K1C untreated rats; P<0.05). All treatments prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats (P<0.05). Aortas from 2K1C rats showed higher MMP-2 levels when compared with sham and all treatments attenuated 2K1C hypertension-induced increases in MMP-2 levels (both P<0.05). Increased gelatinolytic activity (20.6±0.9 vs. 13.9±1.2 A.U.; arbitrary units) co-localized with upregulated aortic MMP-2 expression (8.1±0.3 vs. 5.4±0.4 A.U.) in 2K1C vs. control rats. ATORVA, SILD, or both drugs lowered gelatinolytic activity to 14.6±0.5, 14.6±1.0 and 14.5±0.8 A.U. and lowered the aortic MMP-2 expression to 5.8±0.3, 5.9±0.5 and 5.5±0.5 A.U., respectively. However, these drugs had no in vitro effects on human recombinant MMP-2 activity (P>0.05). Hypertension induced oxidative stress assessed with dihydroethidium probe (7.9±1.2 vs. 16.5±1.5 A.U. in sham vs 2K1C), which was attenuated by ATORVA, SILD or both (9.9±0.3, 10.4±1.5 and 9.6±0.6 A.U., respectively). Plasma malondialdehyde levels paralleled dihydroethidium results. Treatment with ATORVA or SILD, or both, exert antihypertensive effects and prevents 2K1C hypertension-induced vascular remodeling and oxidative stress. These effects were associated with lower MMP-2 levels possibly resulting of antioxidants effects. Our results suggest that ATORVA and SILD may prevent the vascular alterations of hypertension.Supported by FAPESP, Cnpq.