TNF-alpha inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure

Author(s)

Mattos, B. R. ^[1] ; Bonacio, G. F. ^[1] ; Vitorino, T. R. ^[1] ; Garcia, V. T. ^[1] ; Amaral, J. H. ^[2] ; Dellalibera-Joviliano, R. ^{[3, 4]} ; Franca, S. C. ^[1] ; Tanus-Santos, J. E. ^[2] ; Rizzi, E. ^[1]

Affiliation

^[1] Univ Ribeirao Preto, Unit Biotechnol, UNAERP, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, Sao Paulo - Brazil

^[3] Univ Ribeirao Preto, Fac Med, UNAERP, Ribeirao Preto - Brazil

^[4] Univ Estado Minas Gerais, UEMG, Belo Horizonte, MG - Brazil

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 180, OCT 2020.
• Web of Science Citations: 1

Abstract

Systemic arterial hypertension is a public health problem associated with an increased risk of cardiovascular disease. Matrix metalloproteinases (MMP) are endopeptidases that participate in hypertension-induced cardiovascular remodeling, which may be activated by oxidative stress. Angiotensin II (Ang II), a potent hypertrophic and vasoconstrictor peptide, increases oxidative stress, MMP-2 activity and tumor necrosis factor (TNF-alpha) expression. In vitro studies have shown that TNF-alpha is essential for Ang II-induced MMP-2 expression. Thus, this study evaluated whether TNF-alpha inhibition decreases the development of hypertension-induced vascular remodeling via reduction of MMP-2 activity and reactive oxygen species (ROS) formation. Two distinct pharmacological approaches were used in the present study: Pentoxifylline (PTX), a non-selective inhibitor of phosphodiesterases that exerts anti- inflammatory effects via inhibition of TNF-alpha, and Etanercept (ETN), a selective TNF-alpha inhibitor. 2-kidney and 1-Clip (2K1C). 2-kidney and 1-Clip (2K1C) and Sham rats were treated with Vehicle, PTX (50 mg/Kg and 100 mg/kg daily) or ETN (0.3 mg/Kg and 1 mg/kg; three times per week). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. Plasma TNF-alpha and IL-1 beta levels were evaluated by enzyme-linked immunosorbent assay (ELISA) technique. The vascular hypertrophy was examined in the aorta sections stained with hematoxylin/eosin. ROS in aortas was evaluated by dihydroethidium and chemiluminescence lucigenin assay. Aortic MMP-2 levels and activity were evaluated by gel zymography and in situ zymography, respectively. The 2K1C animals showed a progressive increase in SBP levels and was accompanied by significant vascular hypertrophy (p < 0.05 vs Sham). Treatment with PTX at higher doses decreased SBP and vascular remodeling in 2K1C animals (p < 0.05 vs 2K1C vehicle). Although the highest dose of ETN treatment did not reduce blood pressure, the vascular hypertrophy was significantly attenuated in 2K1C animals treated with ETN1 (p < 0.05). The increased cytokine levels and ROS formation were reversed by the highest doses of both PTX and ETN. The increase in MMP-2 levels and activity in 2K1C animals were reduced by PTX100 and ETN1 treatments (p < 0.05 vs vehicle 2K1C). Lower doses of PTX and ETN did not affect any of the evaluated parameters in this study, except for a small reduction in TNF-alpha levels. The findings of the present study suggest that PTX and ETN treatment exerts immunomodulatory effects, blunted excessive ROS formation, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement of vascular remodeling typically found in 2K1C hypertension. Therefore, strategies using anti-hypertensive drugs in combination with TNF alpha inhibitors could be an attractive therapeutic approach to tackle hypertension and its associated vascular remodeling. (AU)

• FAPESP's process: 16/13778-8 - Efects of TNF-alpha inhibition on morphofunctional vascular alterations associated with renovascular hypertension
• Grantee: Elen Rizzi Sanchez
• Support Opportunities: Regular Research Grants