The mechanism that leads to a decrease in β1-adrenergic receptor (β1AR) expression in the failing heart remains uncertain. This study shows that cardiomyocyte β1AR expression and isoproterenol responsiveness decrease in response to oxidative stress. Studies of mechanisms show that the redox-dependent decrease in β1AR expression is uniquely prevented by carvedilol and not other βAR ligands. Carvedilol also promotes the accumulation of N-terminally truncated β1ARs that confer protection against doxorubicin-induced apoptosis in association with activation of protein kinase B. The redox-induced molecular controls for cardiomyocyte β1ARs and pharmacologic properties of carvedilol identified in this study have important clinical and therapeutic implications.
Keywords: AKT; AKT, protein kinase B; CREB, cyclic adenosine monophosphate binding response element protein; ERK, extracellular regulated kinase; FL, full-length; GFX, GF109203X; GRK, G protein–coupled receptor kinase; HF, heart failure; PKA, protein kinase A; PKC, protein kinase C; PTX, pertussis toxin; ROS, reactive oxygen species; cAMP, cyclic adenosine monophosphate; cardiomyocytes; cardioprotection; oxidant stress; β1-adrenergic receptor; βAR, β-adrenergic receptor.