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Mol Ther. 2014 Jan;22(1):178-85. doi: 10.1038/mt.2013.200. Epub 2013 Sep 3.

Cardiac progenitor cells engineered with βARKct have enhanced β-adrenergic tolerance.

Author information

1
San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
2
Center for Translational Medicine, Temple University School of Medicine, 941 MERB, 3500 N Broad St., Philadelphia, Pennsylvania, USA.

Abstract

Stem cell survival and retention in myocardium after injury following adoptive transfer is low. Elevated catecholamine levels coinciding with myocardial injury adversely affect cardiac progenitor cell (CPC) survival. The G protein-coupled receptor kinase 2 (GRK2)-derived inhibitory peptide, βARKct, enhance myocyte contractility, survival, and normalize the neurohormonal axis in failing heart, however salutary effects of βARKct on CPC survival and proliferation are unknown. Herein, we investigated whether the protective effects of βARKct expression seen in the failing heart relate to CPCs. Modified CPCs expressing βARKct enhanced AKT/eNOS signaling through protective β2-adrenergic receptors (β2-ARs). In addition, to the actions of βARKct expression on β2- AR signaling, pharmacologic inhibition of GRK2 also increased β2-AR signaling in nonengineered CPCs (lacking βARKct) but had limited effects in βARKct engineered CPCs providing evidence for the strength of the βARKct in inhibiting GRK2 in these cells. Increased proliferation and metabolic activity were observed in βARKct-engineered CPCs following catecholamine stimulation indicating improved adrenergic tolerance. βARKct modification of CPCs increased survival and proliferation following adoptive transfer in an acute myocardial infarction model concomitant with increased expression of β-AR. Thus, βARKct engineering of CPCs promotes survival and proliferation of injected cells following myocardial infarction, which includes improved β-adrenergic tolerance essential for stem cell survival.

PMID:
24002692
PMCID:
PMC3978798
DOI:
10.1038/mt.2013.200
[Indexed for MEDLINE]
Free PMC Article

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