Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension

Abstract

Mounting evidence indicates that structural and functional vascular changes associated with two-kidney, one-clip (2K-1C) hypertension result, at least in part, from altered activity of matrix metalloproteinases (MMPs). Because MMPs are upregulated by increased formation of reactive oxygen species (ROS), we hypothesized that antioxidant approaches could attenuate the increases in MMP-2 expression/activity and the vascular dysfunction and remodeling associated with 2K-1C hypertension. Sham-operated or 2K-1C hypertensive rats were treated with tempol 18 mg/kg/day or apocyanin 25 mg/kg/day (or vehicle). Systolic blood pressure was monitored weekly. After 8 weeks of treatment, aortic rings were isolated to assess endothelium-dependent and -independent relaxation. Quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin sections. Aortic and systemic ROS levels were measured using dihydroethidine and thiobarbituric acid-reactive substances, respectively. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry, and immunohistochemistry. Tempol and apocyanin attenuated 2K-1C hypertension (181+/-20.8 and 192+/-17.6 mm Hg, respectively, versus 213+/-18 mm Hg in hypertensive controls; both p<0.05) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Tempol, but not apocyanin (p>0.05), prevented the vascular remodeling found in 2K-1C rats (all p<0.01). Tempol was more effective than apocyanin in attenuating hypertension-induced increases in oxidative stress (both p<0.05), MMP-2 levels, and MMP-2 activity in hypertensive rats (all p<0.05). Our results suggest that antioxidant approaches decrease MMP-2 upregulation and attenuate the vascular dysfunction and remodeling during 2K-1C hypertension.

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

“…To our knowledge, no previous study has examined whether MMP-2 polymorphisms or haplotypes are associated with hypertension, although experimental evidence has implicated MMP-2 in the pathogenesis of hypertension [24][25][26][27] and in hypertensive LVH. 8 Previous studies suggest that genetic polymorphisms modify MMP-2 expression or activity.…”

Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children

“…These results confirm that obesity is associated with increased oxidative stress and may have important implications. In fact, oxidative stress is a major MMPs activator 30 and therefore may potentiate MMPs activities in obese subjects. However, the lack of significant differences between genotype or haplotype groups, as reported here, suggest that MMP-9 polymorphisms do not interact significantly with oxidative stress to modulate MMP-9 levels in obese subjects.…”

Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats

“…Among them, MMP-2 and -9, also known as gelatinases A and B, are responsible for degradation of basement membrane elements (mainly collagen IV and laminin) and digestion of collagen I fibrils (gelatin) (21,37). Increased MMP-2 activity in vessels has been reported in many models of hypertension and is associated with vascular remodeling (6,12,19). Doxycycline (DOX), a tetracycline antibiotic and nonspecific MMP inhibitor, was shown to prevent remodeling in aorta of the 2-kidney, 1-clip model of hypertension (4,5).…”