Myocardial oxidative stress contributes to transgenic β 2- adrenoceptor activation-induced cardiomyopathy and heart failure

Background and purpose: Whilst maintaining cardiac performance, chronic beta-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by NADPH oxidase and reactive oxygen species (ROS) after chronic beta(2) -adrenoceptor activation. Experimental approach: Mice with transgenic beta(2) -adrenoceptor overexpression (beta(2) -TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 MAPK, pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. Key results: beta(2) -TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. beta(2) -Adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and..