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, Michael McGregor, Natalie Gude, Roberto Alvarez, Douglas G. Tilley, Walter J. Koch, Mark A. Sussman

Research output: Contribution to journalArticle

Abstract

RATIONALE:: Short-term β-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 β-adrenergic drive on CPC survival and proliferation are unknown. OBJECTIVE:: We sought to determine the relationship between β-adrenergic activity and regulation of 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, 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 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 on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors.

Original languageEnglish
Pages (from-to)476-486
Number of pages11
JournalCirculation Research
Volume112
Issue number3
DOIs
Publication statusPublished - Feb 1 2013

Keywords

  • adrenergic receptors
  • adrenergic regulation
  • adult stem cells
  • cardiac progenitor cells
  • heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Khan, M., Mohsin, S., Avitabile, D., Siddiqi, S., Nguyen, J., Wallach, K., Quijada, P., McGregor, M., Gude, N., Alvarez, R., Tilley, D. G., Koch, W. J., & Sussman, M. A. (2013). β-adrenergic regulation of cardiac progenitor cell death versus survival and proliferation. Circulation Research, 112(3), 476-486. https://doi.org/10.1161/CIRCRESAHA.112.280735