Atorvastatin inhibits pro-inflammatory actions of aldosterone in vascular smooth muscle cells by reducing oxidative stress

Thiago Bruder-Nascimento,Glaucia E Callera,Augusto C Montezano,Eric J Belin De Chantemele,Rita C Tostes,Rhian M Touyz

doi:10.1016/j.lfs.2019.01.043

Abstract

Vascular inflammatory responses play an important role in several cardiovascular diseases. Of the many pro-inflammatory vasoactive factors implicated in this process, is aldosterone, an important mediator of vascular oxidative stress. Statins, such as atorvastatin, are cholesterol-lowering drugs that have pleiotropic actions, including anti-oxidant properties independently of their cholesterol-lowering effect. This study investigated whether atorvastatin prevents aldosterone-induced VSMC inflammation by reducing reactive oxygen species (ROS) production. Vascular smooth muscle cells (VSMC) from WKY rats were treated with 1 μM atorvastatin for 60 min or for 72 h prior to aldosterone (10-7 mol/L) stimulation. Atorvastatin inhibited Rac1/2 and p47phox translocation from the cytosol to the membrane, as well as reduced aldosterone-induced ROS production. Atorvastatin also attenuated aldosterone-induced vascular inflammation and macrophage adhesion to VSMC. Similarly EHT1864, a Rac1/2 inhibitor, and tiron, ROS scavenger, reduced macrophage adhesion. Through its inhibitory effects on Rac1/2 activation and ROS production, atorvastatin reduces vascular ROS generation and inhibits VSMC inflammation. Our data suggest that in conditions associated with aldosterone-induced vascular damage, statins may have vasoprotective effects by inhibiting oxidative stress and inflammation.

Highlights

Aldosterone is a steroid hormone synthesized mainly in the outer layer of the adrenal cortex, the zona glomerulosa [1], extraadrenal sources of aldosterone have been identified [2]
P47phox translocation from the cytosol to the membrane, which was abrogated by atorvastatin treatment (Figs. 2 and 3)
Major findings in the present study demonstrate that atorvastatin attenuates inflammatory effects induced by aldosterone in Vascular smooth muscle cells (VSMC) by inhibiting Rac1/2 and reducing reactive oxygen species (ROS) production

Summary

Introduction

Aldosterone is a steroid hormone synthesized mainly in the outer layer of the adrenal cortex, the zona glomerulosa [1], extraadrenal sources of aldosterone have been identified [2]. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase, revolutionized the treatment of hypercholesterolemia. Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, decreasing endogenous cholesterol synthesis [6,7]. Statins confer cardiovascular protection, which has been confirmed extensively in experimental and clinical studies [8,9]. In addition to lipid-lowering actions of statins, they exhibit a wide array of cardiovascular effects independently of their lipid-reducing properties [10], the so-called pleiotropic effects. Statins influence redox-sensitive processes through putative antioxidant properties and by inhibiting NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation [10,11]. Since vascular cells express functionally active HMG-CoA reductase [13,14], it is possible that vascular effects of statins may involve local inhibition of this enzyme

Methods

Results

Conclusion