Adrenergic regulation of cardiac myocyte apoptosis

The direct effects of catecholamines on cardiac myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be as sociated with cellular hypertrophy, apoptosis, and alterations in contracti le function. Norepinephrine (NE) signals via alpha- and beta -adrenergic re ceptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardi ac myocytes in vitro demonstrate that stimulation of beta (1)-AR induces ap optosis which is cAMP-dependent and involves the voltage-dependent calcium influx channel. In contrast, stimulation Of beta (2)-AR exerts an anti-apop totic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of alpha (1)-AR causes myocyte hypertrophy and may exe rt an anti-apoptotic action. In transgenic mice, myocardial overexpression of either beta (1)-AR or G alphas is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression Of bet a (2)-AR at low levels results in improved cardiac function, whereas expres sion at high levels leads to dilated cardiomyopathy. Overexpression of wild type alpha (1B)-AR does not result in apoptosis, whereas overexpression of G alphaq results in myocyte hypertrophy and/or apoptosis depending on the l evel of expression. Differential activation of the members of the mitogen-a ctivated protein kinase (MAPK) superfamily and production of reactive oxyge n species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes curre nt knowledge about the molecular and cellular mechanisms involved in the re gulation of cardiac myocyte apoptosis via stimulation of adrenergic recepto rs and their coupled effector pathways. (C) 2001 Wiley-Liss, Inc.