Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes

J Mol Cell Cardiol. 2002 Jul;34(7):823-31. doi: 10.1006/jmcc.2002.2020.

Abstract

We have previously reported that beta-adrenergic receptor (beta-AR) stimulation promotes apoptosis in adult ventricular myocytes through PKCepsilon-mediated suppression of ERK. In this study, we investigated differential effects of beta-AR subtypes on this signal pathway. The apoptosis induced by the non-specific beta-AR agonist isoproterenol was largely blocked by the beta(1)-selective antagonist CGP 20712A, but not by the beta(2)-selective antagonist ICI 118551. A pro-apoptotic effect of beta(1)-AR was also blocked by the PKA inhibitor H89, while the protein kinase A (PKA) activators forskolin and dibutyryl-cAMP both induced apoptosis. These results indicate that beta(1)-AR-mediated PKA activation is largely responsible for the apoptosis induced by beta-AR in adult rat cardiac myocytes. This conclusion was also supported by the finding that PKA was preferentially activated by beta(1)-AR over beta(2)-AR. beta(2)-AR selectively induced anti-apoptotic ERK activation in the presence of PKCepsilon suppression, and this ERK activation was sensitive to pertussis toxin. PKCepsilon itself as well as Akt, the other anti-apoptotic factor were activated by both beta-AR subtypes. Thus, beta(1)-AR induces pro-apoptotic signals mainly through PKA activation. In contrast, beta(2)-AR is linked to Gi-mediated ERK activation, which is involved in the anti-apoptotic pathway, and is regulated by PKCepsilon. Therefore, our findings suggest a rather complex role for beta-AR subtypes in the regulation of apoptosis in adult ventricular myocytes.

Publication types

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

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Apoptosis / physiology*
  • GTP-Binding Proteins / metabolism
  • Isoenzymes / metabolism
  • Isoproterenol / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • Myocytes, Cardiac / physiology*
  • Protein Kinase C / metabolism
  • Protein Kinase C-epsilon
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Receptors, Adrenergic, beta / classification
  • Receptors, Adrenergic, beta / physiology*

Substances

  • Adrenergic beta-Agonists
  • Isoenzymes
  • Proto-Oncogene Proteins
  • Receptors, Adrenergic, beta
  • Prkce protein, rat
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • Isoproterenol