Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes.
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.
Shizukuda
Yukitaka
Y
Section of Cardiology, Department of Medicine, University of Illinois at Chicago, Illinois 60612, USA. shizukud@uic.edu
Buttrick
Peter M
PM
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000145:classification / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011943:Receptors, Adrenergic, beta; C497257:Prkce protein, rat; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D007545:Isoproterenol