Differential cardiac gene expression in atorvastatin‐treated dogs

Abstract

Statins have been shown to increase NO synthesis and to inhibit the small GTP-binding protein rac1 and NADPH oxidase. This study was undertaken to determine the changes in gene expression in dogs given atorvastatin (3 mg/kg/day) for 14 days by microarray. No change in hemodynamic parameters was observed. Plasma cholesterol fell from 158 ± 38 to 128 ± 26 mg/dl (P<0.05). Left ventricle (LV) was harvested from control (C) and atorvastatin-treated (A) dogs. Bradykinin 10−4M induced a NO-dependent reduction of LV oxygen consumption (C: −35.9 ± 1.5 %, n=5; A: −33.2 ± 1.9%, n=9). The activation of NADPH oxidase by angiotensin-II similarly reduced the effect of bradykinin in control (−19.9 ± 1.9%, n=5) and atorvastatin-treated dogs (−18.1 ± 4.3%, n=8), suggesting that NADPH oxidase activity was not decreased. eNOS and Rac-1 protein expression was not altered. Cardiac RNA was extracted from 4 dogs of each group to determine the changes in gene expression. eNOS, iNOS, nNOS, SOD1, p22, p47 and gp91 were not altered, whereas SOD3 was increased by 1.5 fold (p<0.01). Interestingly, some genes involved in the modulation of the GTP-binding proteins activity were differentially expressed: Rho-GTPase activating protein 7 (GAP) was increased (2.6 fold, p<0.01), whereas obscurin, with a guanine exchange factor domain (GEF), was decreased (14.6 fold, p<0.01). Furthermore, microarray data showed a marked changes in cardiac gene expression.