Nitrite treatment downregulates vascular MMP‐2 activity and inhibits vascular remodeling in hypertension independently of its antihypertensive effects

Abstract

ABSTRACT Hypertension is associated with cardiovascular remodeling. Given that impaired redox state activates matrix metalloproteinase (MMP)− 2 and promotes vascular remodeling, we hypothesized that nitrite treatment at a non‐antihypertensive dose exerts antioxidant effects and attenuates both MMP‐2 activation and vascular remodeling of hypertension. We examined the effects of oral sodium nitrite at antihypertensive (15 mg/kg) or non‐antihypertensive (1 mg/kg) daily dose in hypertensive rats (two kidney, one clip; 2K1C model). Sham‐operated and 2K1C hypertensive rats received vehicle or nitrite by gavage for four weeks. Systolic blood pressure decreased only in hypertensive rats treated with nitrite 15 mg/Kg/day. Both low and high nitrite doses decreased 2K1C‐induced vascular remodeling assessed by measuring aortic cross‐sectional area, media/lumen ratio, and number of vascular smooth muscle cells/aortic length. Both low and high nitrite doses decreased 2K1C‐induced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay. Vascular MMP‐2 expression and activity were assessed by gel zymography, Western blot, and in situ zymography increased with hypertension. While MMP‐2 levels did not change in response to both doses of nitrite, both doses completely prevented hypertension‐induced increases in vascular MMP activity. Moreover, incubation of aortas from hypertensive rats with nitrite at 1–20 &mgr;mol/L reduced gelatinolytic activity by 20–30%. This effect was fully inhibited by the xanthine oxidase (XOR) inhibitor febuxostat, suggesting XOR‐mediated generation of nitric oxide (NO) from nitrite as a mechanism explaining the responses to nitrite. In vitro incubation of aortic extracts with nitrite 20 &mgr;mol/L did not affect MMP‐2 activity. These results show that nitrite reverses the vascular structural alterations of hypertension, independently of anti‐hypertensive effects. This response is mediated, at least in part, by XOR and is attributable to antioxidant effects of nitrite blunting vascular MMP‐2 activation. Our findings suggest nitrite therapy to reverse structural alterations of hypertension. Graphical abstract Figure. No Caption available. HighlightsHypertension promotes vascular remodeling.We investigated the effects of nitrite on vascular remodeling of hypertension.Nitrite exerted antioxidant effects and inhibited vascular MMP‐2 activity.Antioxidant effects of nitrite inhibit MMP‐2 and vascular remodeling of hypertension.