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 language | English |
|---|---|
| Pages (from-to) | H1622-H1648 |
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 310 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2016 |
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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)
Cite this
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; Miragoli, Michele; Di Pasquale, Elisa; Stirparo, Giuliano G.; Mastrototaro, Giuseppina; Urbanek, Konrad; De Angelis, Antonella; Macchi, Emilio; Stilli, Donatella; Quaini, Federico; Musso, Ezio.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 310, No. 11, 01.06.2016, p. H1622-H1648.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart
AU - Savi, Monia
AU - Bocchi, Leonardo
AU - Rossi, Stefano
AU - Frati, Caterina
AU - Graiani, Gallia
AU - Lagrasta, Costanza
AU - Miragoli, Michele
AU - Di Pasquale, Elisa
AU - Stirparo, Giuliano G.
AU - Mastrototaro, Giuseppina
AU - Urbanek, Konrad
AU - De Angelis, Antonella
AU - Macchi, Emilio
AU - Stilli, Donatella
AU - Quaini, Federico
AU - Musso, Ezio
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Cardiac gap junction connexions
KW - Cardiac progenitor cells
KW - Growth factors and cytokines
KW - Myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=84983803017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983803017&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00035.2015
DO - 10.1152/ajpheart.00035.2015
M3 - Article
AN - SCOPUS:84983803017
VL - 310
SP - H1622-H1648
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 11
ER -