Adrenergic regulation of cardiac myocyte apoptosis

Abstract

The direct effects of catecholamines on cardiac myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be associated with cellular hypertrophy, apoptosis, and alterations in contractile function. Norepinephrine (NE) signals via a-and b-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that stimulation of b 1 -AR induces apoptosis which is cAMPdependent and involves the voltage-dependent calcium in¯ux channel. In contrast, stimulation of b 2 -AR exerts an anti-apoptotic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of a 1 -AR causes myocyte hypertrophy and may exert an anti-apoptotic action. In transgenic mice, myocardial overexpression of either b 1 -AR or Gas is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression of b 2 -AR at low levels results in improved cardiac function, whereas expression at high levels leads to dilated cardiomyopathy. Overexpression of wildtype a 1B -AR does not result in apoptosis, whereas overexpression of Gaq results in myocyte hypertrophy and/or apoptosis depending on the level of expression. Differential activation of the members of the mitogen-activated protein kinase (MAPK) superfamily and production of reactive oxygen species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes current knowledge about the molecular and cellular mechanisms involved in the regulation of cardiac myocyte apoptosis via stimulation of adrenergic receptors and their coupled effector pathways.

Glycogen synthase kinase-3β plays a pro-apoptotic role in β-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of β1 integrins

“…β-AR stimulation induces cardiac myocyte apoptosis in vitro and in vivo [4]. β1 integrins protect ARVM against β-AR stimulated apoptosis [5,6].…”

“…The data presented here demonstrate that BAPTA-AM inhibits β-AR stimulated increases in tyrosine phosphorylation and activity of GSK-3β. β-AR stimulation is known regulate Ca 2+ entry via L-type Ca 2+ channels in adult heart [4]. Inhibition of L-type Ca 2+ channels is shown to inhibit βAR-stimulated apoptosis in ARVM [4].…”

“…This analysis demonstrated that β-AR stimulation (15 min) increases tyr 216 phosphorylation of GSK-3β (Fig 2A). β-AR-stimulated apoptosis in ARVM requires calcium entry via voltagedependent calcium channels [4]. Calcium-dependent kinase, pyk2, is suggested to increase tyr 216 phosphorylation and activity of GSK-3β in neuronal cells [12].…”

Khat (Catha edulis)-induced apoptosis is inhibited by antagonists of caspase-1 and -8 in human leukaemia cells

“…Amphetamine has been shown to induce apoptosis in fetal rat neocortical neurons (Stumm et al, 1999) and in PC12 cells (Oliveira et al, 2002) in a process generally considered to be associated with increased stress and formation of reactive oxygen substances. Moreover, the ephedrine-related catecholamine, norepinephrine, induces apoptosis in cardiac myocytes (Singh et al, 2001) by binding to b-adrenergic receptors through a mechanism that is dependent on activation of cyclic AMP-dependent protein kinase (Mann et al, 1992;Communal et al, 2000).…”

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

“…Most parenteral inotropes share the common end point of increasing cAMP levels in the cardiomyocyte leading to increased calcium influx into the cell that in turn stimulates myocyte contractility 4. Cardiomyocyte loading of calcium increases myocardial contractile force, oxygen consumption, and apoptotic signaling 5, 6, 7. Therefore, despite demonstrated improvements in cardiac function and hemodynamics, the use of inotropes in HFrEF has been demonstrated to have deleterious effects in both the hospital and outpatient setting 8, 9…”