title: Cardiac progenitor cells engineered with βARKct have enhanced β-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, 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.
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Alkatib
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Truffa
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, 941 MERB, 3500 N Broad St., Philadelphia, Pennsylvania, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Chuprun
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, 941 MERB, 3500 N Broad St., Philadelphia, Pennsylvania, USA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, 941 MERB, 3500 N Broad St., Philadelphia, Pennsylvania, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000737:chemistry / Q000235:genetics*; D015870:Gene Expression; D006321:Heart / Q000187:drug effects; D006801:Humans; D051379:Mice; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014161:Transduction, Genetic
chemical_list: D002395:Catecholamines; D010446:Peptide Fragments; D018342:Receptors, Adrenergic, beta-1; D054769:G-Protein-Coupled Receptor Kinase 2