β2-Adrenergic receptor-induced transactivation of epidermal growth factor receptor and platelet-derived growth factor receptor via Src kinase promotes rat cardiomyocyte survival.

Chronic stimulation of the β-AR (adrenergic receptor) promotes apoptosis of cardiomyocytes, which is implicated in cardiac dysfunction. β1-AR and β2-AR are the main subtypes of β-AR that exert distinct effects on the survival of cardiomyocytes. To clarify the physiological roles of β1-AR and β2-AR in cardiomyocytes, the effects of β1-AR or β2-AR knockdown on the survival of H9c2 cardiomyocytes was investigated. Knockdown of β2-AR, but not β1-AR, suppressed the phosphorylation of EGFR (epidermal growth factor receptor) and PDGFR (platelet-derived growth factor receptor) induced by ISO (isoprenaline). The EGFR inhibitor, AG1478, attenuated ERK (extracellular-signal-regulated kinase) activation and partially decreased cell survival. Pretreatment with AG1296, a PDGFR inhibitor, abolished ISO-induced Akt (also known as protein kinase B) phosphorylation and led to a decrease in cell viability. In addition, the Src tyrosine kinase inhibitor, PP2, blocked ISO-mediated both Akt and ERK activation and heavily suppressed viability. Accordingly, in primary neonatal rat cardiomyocytes, the β2-AR inhibitor, but not the β1-AR inhibitor, abrogated the transactivation of EGFR and PDGFR, which was respectively related to Akt and ERK activation. The results show that β2-AR transactivates PDGFR and EGFR, thereby promoting survival of cardiomyocytes.