Abstract
Hypertension-induced vascular remodeling is associated with oxidative stress, and matrix metalloproteinase (MMP) and TGF (transforming growth factor)-beta up-regulation. Atorvastatin (ATORVA) and sildenafil (SILD) exert pleiotropic effects that may result in cardiovascular protection. We evaluated the effects of ATORVA and SILD alone or in association on oxidative stress, MMPs and TGF-beta up-regulation, and vascular hypertrophy induced by 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were orally 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±7, 156±5, and 138±4 mmHg, respectively, vs. 207±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). Hypertension increased NADPH oxidase activity when compared with control groups and the treatments reduced oxidative stress. Aortas from 2K1C rats showed higher MMP-2 levels when compared with sham (0.399±0.06 vs. 0.173±0.05 A.U.) and all treatments attenuated 2K1C hypertension-induced increases in MMP-2 levels (ATORVA: 0.191±0.04; SILD: 0.136±0.05; ATORVA+SILD: 0.173±0.03; P<0.05). However, these drugs had no in vitro effects on human recombinant MMP-2 activity (P>0.05). Moreover, 2K1C rats showed higher MMP-9 (12.64±0.86 vs. 8.70±0.92) and TGF-beta expression (14.25±0.97 vs. 9.07±1.67) compared with sham groups. All treatments prevented 2K1C hypertension-induced increases in these pro-fibrotic factors. Treatment with ATORVA or SILD, or both, exerted antihypertensive effects and prevented 2K1C hypertension-induced vascular remodeling through antioxidant and anti-fibrotic mechanisms. Our results suggest that ATORVA and SILD may prevent the vascular alterations of hypertension.
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