β-Adrenergic receptor blockade modulates Bcl-XS expression and reduces apoptosis in failing myocardium

Sumanth D. Prabhu, Guangwu Wang, Jianzhu Luo, Yan Gu, Peipei Ping, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

The mechanisms by which β-adrenergic receptor (β-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of β-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-XS) and anti-apoptotic (Bcl-XLand Bcl-2) gene expression, and Bcl-XL 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-XS mRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-XL mRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-XS staining in failing myocardium, with unchanged Bcl-XL. 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-XS expression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-XL. Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-XS protein, reducing the Bcl-XL/XS ratio and myocyte survival (P < 0.005). ISO-induced Bcl-XS expression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a β1-AR selective antagonist, but not by ICI118,551, a β2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-XS expression via the β1-AR. β-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-XS expression may be one mechanism underlying this effect.

Original languageEnglish
Pages (from-to)483-493
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume35
Issue number5
DOIs
StatePublished - May 1 2003

Keywords

  • Apoptosis
  • Bcl-X
  • Cell signaling
  • Heart failure
  • β-Adrenergic antagonists

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