β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation

Rationale: Short-term beta-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term beta-adrenergic drive on CPC survival and proliferation are unknown. Objective: We sought to determine the relationship between beta-adrenergic activity and regulation of CPC function. Methods and Results: Mouse and human CPCs express only beta 2 adrenergic receptor (beta 2-AR) in conjunction with stem cell marker c-kit. Activation of beta 2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein-coupled receptor kinase 2. Conversely, silencing of beta 2-AR expression or treatment with beta 2-antagonist ICI 118, 551 impairs CPC proliferation and survival. beta 1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of beta 1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium. Conclusions: beta-adrenergic stimulation promotes expansion and survival of CPCs through beta 2-AR, but acquisition of beta 1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors. (Circ Res. 2013;112:476-486.)