Cardiac progenitor cells engineered with ßARKct have enhanced ß-adrenergic tolerance.

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, ßARKct, enhance myocyte contractility, survival, and normalize the neurohormonal axis in failing heart, however salutary effects of ßARKct on CPC survival and proliferation are unknown. Herein, we investigated whether the protective effects of ßARKct expression seen in the failing heart relate to CPCs. Modified CPCs expressing ßARKct enhanced AKT/eNOS signaling through protective ß2-adrenergic receptors (ß2-ARs). In addition, to the actions of ßARKct expression on ß2- AR signaling, pharmacologic inhibition of GRK2 also increased ß2-AR signaling in nonengineered CPCs (lacking ßARKct) but had limited effects in ßARKct engineered CPCs providing evidence for the strength of the ßARKct in inhibiting GRK2 in these cells. Increased proliferation and metabolic activity were observed in ßARKct-engineered CPCs following catecholamine stimulation indicating improved adrenergic tolerance. ßARKct modification of CPCs increased survival and proliferation following adoptive transfer in an acute myocardial infarction model concomitant with increased expression of ß-AR. Thus, ßARKct engineering of CPCs promotes survival and proliferation of injected cells following myocardial infarction, which includes improved ß-adrenergic tolerance essential for stem cell survival.