1. Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart
- Author
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Antonella De Angelis, Costanza Lagrasta, Gallia Graiani, Ezio Musso, Elisa Di Pasquale, Caterina Frati, Giuseppina Mastrototaro, Giuliano Giuseppe Stirparo, Konrad Urbanek, Leonardo Bocchi, Michele Miragoli, Federico Quaini, Donatella Stilli, Monia Savi, Stefano Rossi, Emilio Macchi, Savi, Monia, Bocchi, Leonardo, Rossi, Stefano, Frati, Caterina, Graiani, Gallia, Lagrasta, Costanza, Miragoli, Michele, Di Pasquale, Elisa, Stirparo, Giuliano G., Mastrototaro, Giuseppina, Urbanek, Konrad, DE ANGELIS, Antonella, Macchi, Emilio, Stilli, Donatella, Quaini, Federico, Musso, Ezio, Lagrasta, Costanza Anna Maria, Pasquale, Elisa Di, Urbanek, KONRAD ARKADIUSZ, Angelis, Antonella De, and Musso, Ezio Maria Rosmino
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Cardiac progenitors ,Physiology ,medicine.medical_treatment ,Cardiac gap junction connexion ,030204 cardiovascular system & hematology ,Cardiac progenitor cell ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Animals ,Medicine ,Myocytes, Cardiac ,Myocardial infarction ,Insulin-Like Growth Factor I ,Rats, Wistar ,Hepatocyte Growth Factor ,business.industry ,Stem Cells ,Growth factor ,Growth factors and cytokine ,medicine.disease ,cardiac gap junction connexin ,Rats ,030104 developmental biology ,Connexin 43 ,Infarcted heart ,Cardiology ,Hepatocyte growth factor ,Antiarrhythmic effect ,Cardiology and Cardiovascular Medicine ,business ,Local injection ,Anti-Arrhythmia Agents ,Arrhythmia ,medicine.drug - Abstract
c-Kitpos 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.
- Published
- 2016