Beta-adrenergic receptor blockade modulates Bcl-X(S) expression and reduces apoptosis in failing myocardium

J Mol Cell Cardiol. 2003 May;35(5):483-93. doi: 10.1016/s0022-2828(03)00052-x.


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-X(S) 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 beta1-AR selective antagonist, but not by ICI118,551, a beta2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-X(S) expression via the beta1-AR. beta-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-X(S) expression may be one mechanism underlying this effect.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Apoptosis / drug effects*
  • Heart / drug effects*
  • Heart Failure / drug therapy
  • Proto-Oncogene Proteins c-bcl-2 / drug effects*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / drug effects
  • Rats
  • Ventricular Remodeling / drug effects
  • bcl-X Protein


  • Adrenergic beta-Antagonists
  • Bcl2l1 protein, rat
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • bcl-X Protein