β-adrenergic receptor blockade modulates Bcl-Xs expression and reduces apoptosis in failing myocardium

The mechanisms by which beta-adrenergic receptor (beta-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of beta-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-X-s) and anti-apoptotic (Bcl-X(L)and Bcl-2) gene expression, and Bcl-X-L and Bcl-Xs protein in post-infarction HF in rats. In untreated rats, there was significant (P < 0.001) LV dilatation and systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P < 0.005). Fas, Bax, and Bcl-2 mRNA expression was unchanged. However, Fas ligand mRNA and Bcl-X-s mRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-X-L mRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-X-s staining in failing myocardium, with unchanged Bcl-X-L. Metoprolol treatment resulted in: (1) improved LV remodeling (P < 0.025), (2) reduced myocardial apoptosis (P < 0.005), and (3) selective reduction in myocardial Bcl-X-s expression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-X-L. Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-X-s protein, reducing the Bcl-X-L/X-s ratio and myocyte survival (P < 0.005). ISO-induced Bcl-X-s expression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a beta(1)-AR selective antagonist, but not by ICI 118,55 1, a beta(2)-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-X-s expression via the beta(1)-AR. beta-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-X-s expression may be one mechanism underlying this effect. (C) 2003 Elsevier Science Ltd. All rights reserved.