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

Monia Savi, Leonardo Bocchi, Stefano Rossi, Caterina Frati, Gallia Graiani, Costanza Lagrasta, Michele Miragoli, Elisa Di Pasquale, Giuliano G. Stirparo, Giuseppina Mastrototaro, Konrad Urbanek, Antonella De Angelis, Emilio Macchi, Donatella Stilli, Federico Quaini, Ezio Musso

Research output: Contribution to journalArticlepeer-review

Abstract

c-Kitpos cardiac progeni-tor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophys-iological 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 amelio-rating 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 prop-erties were examined by epicardial multiple-lead recording. Hemody-namic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular bi-ology 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 refrac-toriness 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 func-tion and anatomical remodeling were equally improved by all regen-erative 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 Cav 1.2 expression, favoring intercellular coupling and spread of excitation in mended heart.

Original languageEnglish
Pages (from-to)H1622-H1648
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number11
DOIs
Publication statusPublished - Jun 1 2016

Keywords

  • Arrhythmia
  • Cardiac gap junction connexions
  • Cardiac progenitor cells
  • Growth factors and cytokines
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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