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

• Published in: Free radical biology & medicine 2019-01, Vol.130, p.234-243
• Main Authors: Rizzi, Elen, Amaral, Jefferson H., Guimarães, Danielle A., Conde-Tella, Sandra O., Pinheiro, Lucas C., Gerlach, Raquel F., Castro, Michele M., Tanus-Santos, Jose E.
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Antioxidants; Aorta - drug effects; Aorta - pathology; Blood Pressure - drug effects; Disease Models, Animal; Febuxostat - pharmacology; Gene Expression Regulation - drug effects; Humans; Hypertension; Hypertension, Renovascular - drug therapy; Hypertension, Renovascular - genetics; Hypertension, Renovascular - pathology; Matrix Metalloproteinase 2 - genetics; MMP-2; Muscle, Smooth, Vascular - drug effects; Nitric Oxide - metabolism; Nitrite; Nitrites - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Rats; Reactive Oxygen Species; Vascular remodeling; Vascular Remodeling - drug effects; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - genetics
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.11.002

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 μmol/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 μmol/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. [Display omitted] •Hypertension 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.