title: Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart.
abstract: c-Kit(pos) cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF + IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs + GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs + GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs + GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs + GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart.
authors.affiliation: Department of Life Sciences, University of Parma, Italy;
authors.forename: Monia
authors.initials: M
authors.lastname: Savi
authors.affiliation: Department of Life Sciences, University of Parma, Italy;
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bocchi
authors.affiliation: Department of Life Sciences, University of Parma, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Italy;
authors.forename: Caterina
authors.initials: C
authors.lastname: Frati
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Italy;
authors.forename: Gallia
authors.initials: G
authors.lastname: Graiani
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Italy; Cardiac Stem Cell Interdepartmental Center "CISTAC," University of Parma, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lagrasta
authors.affiliation: Humanitas Clinical and Research Center, Rozzano (MI), Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: Miragoli
authors.affiliation: Humanitas Clinical and Research Center, Rozzano (MI), Italy; Institute of Genetic and Biomedical Research-UOS Milan-National Research Council, Milan, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Di Pasquale
authors.affiliation: Humanitas Clinical and Research Center, Rozzano (MI), Italy;
authors.forename: Giuliano G
authors.initials: GG
authors.lastname: Stirparo
authors.affiliation: Humanitas Clinical and Research Center, Rozzano (MI), Italy;
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mastrototaro
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Italy;
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Life Sciences, University of Parma, Italy; Cardiac Stem Cell Interdepartmental Center "CISTAC," University of Parma, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Macchi
authors.affiliation: Department of Life Sciences, University of Parma, Italy; Cardiac Stem Cell Interdepartmental Center "CISTAC," University of Parma, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Stilli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Italy; Cardiac Stem Cell Interdepartmental Center "CISTAC," University of Parma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.affiliation: Department of Life Sciences, University of Parma, Italy; Cardiac Stem Cell Interdepartmental Center "CISTAC," University of Parma, Italy ezio.musso@unipr.it.
authors.forename: Ezio
authors.initials: E
authors.lastname: Musso
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D018031:Connexin 43 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I
keywords: arrhythmia; cardiac gap junction connexins; cardiac progenitor cells; growth factors and cytokines; myocardial infarction