Beta-adrenergic receptor blockade modulates Bcl-X(S) 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-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.
Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA. sprabhu@louisville.edu <sprabhu@louisville.edu>
Sumanth D
SD
Prabhu
Guangwu
G
Wang
Jianzhu
J
Luo
Yan
Y
Gu
Peipei
P
Ping
Bysani
B
Chandrasekar
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D020257:Ventricular Remodeling / Q000187:drug effects; D051020:bcl-X Protein
D000319:Adrenergic beta-Antagonists; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein