Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.

Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Leonardo Bocchi, Monia Savi, Gallia Graiani, Stefano Rossi, Aldo Agnetti, Francesca Stillitano, Costanza Lagrasta, Silvana Baruffi, Roberta Berni, Caterina Frati, Mario Vassalle, Umberto Squarcia, Elisabetta Cerbai, Emilio Macchi, Donatella Stilli, Federico Quaini, Ezio Musso
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2011
Materias:
R
Q
Acceso en línea:https://doaj.org/article/25718372cf8949d1aae3b1a499700e19
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:25718372cf8949d1aae3b1a499700e19
record_format dspace
spelling oai:doaj.org-article:25718372cf8949d1aae3b1a499700e192021-11-18T06:57:05ZGrowth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.1932-620310.1371/journal.pone.0017750https://doaj.org/article/25718372cf8949d1aae3b1a499700e192011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21445273/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.Leonardo BocchiMonia SaviGallia GraianiStefano RossiAldo AgnettiFrancesca StillitanoCostanza LagrastaSilvana BaruffiRoberta BerniCaterina FratiMario VassalleUmberto SquarciaElisabetta CerbaiEmilio MacchiDonatella StilliFederico QuainiEzio MussoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17750 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Leonardo Bocchi
Monia Savi
Gallia Graiani
Stefano Rossi
Aldo Agnetti
Francesca Stillitano
Costanza Lagrasta
Silvana Baruffi
Roberta Berni
Caterina Frati
Mario Vassalle
Umberto Squarcia
Elisabetta Cerbai
Emilio Macchi
Donatella Stilli
Federico Quaini
Ezio Musso
Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
description Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.
format article
author Leonardo Bocchi
Monia Savi
Gallia Graiani
Stefano Rossi
Aldo Agnetti
Francesca Stillitano
Costanza Lagrasta
Silvana Baruffi
Roberta Berni
Caterina Frati
Mario Vassalle
Umberto Squarcia
Elisabetta Cerbai
Emilio Macchi
Donatella Stilli
Federico Quaini
Ezio Musso
author_facet Leonardo Bocchi
Monia Savi
Gallia Graiani
Stefano Rossi
Aldo Agnetti
Francesca Stillitano
Costanza Lagrasta
Silvana Baruffi
Roberta Berni
Caterina Frati
Mario Vassalle
Umberto Squarcia
Elisabetta Cerbai
Emilio Macchi
Donatella Stilli
Federico Quaini
Ezio Musso
author_sort Leonardo Bocchi
title Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
title_short Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
title_full Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
title_fullStr Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
title_full_unstemmed Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
title_sort growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/25718372cf8949d1aae3b1a499700e19
work_keys_str_mv AT leonardobocchi growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT moniasavi growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT galliagraiani growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT stefanorossi growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT aldoagnetti growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT francescastillitano growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT costanzalagrasta growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT silvanabaruffi growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT robertaberni growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT caterinafrati growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT mariovassalle growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT umbertosquarcia growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT elisabettacerbai growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT emiliomacchi growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT donatellastilli growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT federicoquaini growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
AT eziomusso growthfactorinducedmobilizationofcardiacprogenitorcellsreducestheriskofarrhythmiasinaratmodelofchronicmyocardialinfarction
_version_ 1718424156107702272