Subtype Specific Roles of β-Adrenergic Receptors in Apoptosis of Adult Rat Ventricular Myocytes

Y. Shizukuda and P. M. Buttrick. Subtype Specific Roles of β-Adrenergic Receptors in Apoptosis of Adult Rat Ventricular Myocytes. Journal of Molecular and Cellular Cardiology (2002) 34, 823–831. We have previously reported that β-adrenergic receptor (β-AR) stimulation promotes apoptosis in adult ventricular myocytes through PKCε-mediated suppression of ERK. In this study, we investigated differential effects of β-AR subtypes on this signal pathway. The apoptosis induced by the non-specific β-AR agonist isoproterenol was largely blocked by the β1-selective antagonist CGP 20712A, but not by the β2-selective antagonist ICI 118551. A pro-apoptotic effect of β1-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 β1-AR-mediated PKA activation is largely responsible for the apoptosis induced by β-AR in adult rat cardiac myocytes. This conclusion was also supported by the finding that PKA was preferentially activated by β1-AR over β2-AR. β2-AR selectively induced anti-apoptotic ERK activation in the presence of PKC ε suppression, and this ERK activation was sensitive to pertussis toxin. PKC ε itself as well as Akt, the other anti-apoptotic factor were activated by both β-AR subtypes. Thus, β1-AR induces pro-apoptotic signals mainly through PKA activation. In contrast, β2-AR is linked to Gi-mediated ERK activation, which is involved in the anti-apoptotic pathway, and is regulated by PKC ε. Therefore, our findings suggest a rather complex role for β-AR subtypes in the regulation of apoptosis in adult ventricular myocytes.