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Original Research

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

Mohsin 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, Mark A Sussman
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https://doi.org/10.1161/CIRCRESAHA.112.280735
Circulation Research. 2012;CIRCRESAHA.112.280735
Originally published December 14, 2012
Mohsin Khan
San Diego Heart Research Institute, San Diego State University;
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Sadia Mohsin
San Diego Heart Research Institute, San Diego State University;
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Daniele Avitabile
San Diego Heart Research Institute, San Diego State University;
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Sailay Siddiqi
San Diego Heart Research Institute, San Diego State University;
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Jonathan Nguyen
San Diego Heart Research Institute, San Diego State University;
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Kathleen Wallach
San Diego Heart Research Institute, San Diego State University;
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Pearl Quijada
San Diego Heart Research Institute, San Diego State University;
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Micheal Mcgregor
San Diego Heart Research Institute, San Diego State University;
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Natalie Gude
San Diego Heart Research Institute, San Diego State University;
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Roberto Alvarez
San Diego Heart Research Institute, San Diego State University;
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Douglas G Tilley
Center for Translational Medicine, Temple University School of Medicine
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Walter J Koch
Center for Translational Medicine, Temple University School of Medicine
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Mark A Sussman
San Diego Heart Research Institute, San Diego State University;
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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.

  • Adrenergic regulation
  • Adult stem cells
  • Cardiac progenitor cells
  • Heart failure
  • 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 Proliferation
    Mohsin 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 Sussman
    Circulation Research. 2012;CIRCRESAHA.112.280735, originally published December 14, 2012
    https://doi.org/10.1161/CIRCRESAHA.112.280735

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    β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation
    Mohsin 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 Sussman
    Circulation Research. 2012;CIRCRESAHA.112.280735, originally published December 14, 2012
    https://doi.org/10.1161/CIRCRESAHA.112.280735
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