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

Autor: Rizzi E; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil; Biotechnology Unit, Ribeirao Preto University, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Amaral JH; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Guimarães DA; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Conde-Tella SO; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Pinheiro LC; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Gerlach RF; Department of Morphology, Estomatology and Physiology, Dental School of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Castro MM; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil., Tanus-Santos JE; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil. Electronic address: tanus@fmrp.usp.br.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2019 Jan; Vol. 130, pp. 234-243. Date of Electronic Publication: 2018 Nov 03.
DOI: 10.1016/j.freeradbiomed.2018.11.002
Abstrakt: 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.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: