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

Abstract
Rationale: Short term β-adrenergic stimulation promotes contractility in response to stress, but is ultimately detrimental in the failing heart due to accrual of cardiomyocyte death. Endogenous CPC activation may partially offset cardiomyocyte losses, but consequences of long term β-adrenergic drive upon CPC survival and proliferation are unknown.
Objective: We sought to determine the relationship between β-adrenergic activity and regulation of cardiac progenitor cell (CPC) function.
Methods and Results: Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, ERK1/2 and eNOS phosphorylation, up-regulation of cyclin D1, and decreased levels of GRK2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium.
Conclusions: β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR upon commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors.
- Received August 28, 2012.
- Accepted December 14, 2012.
- Copyright © 2012, American Heart Association
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- β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and ProliferationMohsin Khan, Sadia Mohsin, Daniele Avitabile, Sailay Siddiqi, Jonathan Nguyen, Kathleen Wallach, Pearl Quijada, Micheal Mcgregor, Natalie Gude, Roberto Alvarez, Douglas G Tilley, Walter J Koch and Mark A SussmanCirculation Research. 2012;CIRCRESAHA.112.280735, originally published December 14, 2012https://doi.org/10.1161/CIRCRESAHA.112.280735
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- β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and ProliferationMohsin Khan, Sadia Mohsin, Daniele Avitabile, Sailay Siddiqi, Jonathan Nguyen, Kathleen Wallach, Pearl Quijada, Micheal Mcgregor, Natalie Gude, Roberto Alvarez, Douglas G Tilley, Walter J Koch and Mark A SussmanCirculation Research. 2012;CIRCRESAHA.112.280735, originally published December 14, 2012https://doi.org/10.1161/CIRCRESAHA.112.280735