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.

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart / Savi, Monia; Bocchi, Leonardo; Rossi, Stefano; Frati, Caterina; Graiani, Gallia; Lagrasta, Costanza Anna Maria; Miragoli, Michele; Pasquale, Elisa Di; Stirparo, Giuliano G.; Mastrototaro, Giuseppina; Urbanek, Konrad Arkadiusz; Angelis, Antonella De; Macchi, Emilio; Stilli, Donatella; Quaini, Federico; Musso, Ezio Maria Rosmino. - In: AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY. - ISSN 0363-6135. - 310:11(2016), pp. 1622-1648. [10.1152/ajpheart.00035.2015]

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

SAVI, Monia;BOCCHI, Leonardo;ROSSI, Stefano;FRATI, Caterina;GRAIANI, Gallia;LAGRASTA, Costanza Anna Maria;MIRAGOLI, MICHELE;URBANEK, KONRAD ARKADIUSZ;MACCHI, Emilio;STILLI, Donatella;QUAINI, Federico;MUSSO, Ezio Maria Rosmino
2016

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.
Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart / Savi, Monia; Bocchi, Leonardo; Rossi, Stefano; Frati, Caterina; Graiani, Gallia; Lagrasta, Costanza Anna Maria; Miragoli, Michele; Pasquale, Elisa Di; Stirparo, Giuliano G.; Mastrototaro, Giuseppina; Urbanek, Konrad Arkadiusz; Angelis, Antonella De; Macchi, Emilio; Stilli, Donatella; Quaini, Federico; Musso, Ezio Maria Rosmino. - In: AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY. - ISSN 0363-6135. - 310:11(2016), pp. 1622-1648. [10.1152/ajpheart.00035.2015]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2809721
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