hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.

After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-ind...

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Autores principales:	Antti Siltanen, Katsukiyo Kitabayashi, Päivi Lakkisto, Johanna Mäkelä, Tommi Pätilä, Masamichi Ono, Ilkka Tikkanen, Yoshiki Sawa, Esko Kankuri, Ari Harjula
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c66ad6628e44f3797327e5ef929bed1
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spelling	oai:doaj.org-article:0c66ad6628e44f3797327e5ef929bed12021-11-18T06:55:08ZhHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.1932-620310.1371/journal.pone.0019161https://doaj.org/article/0c66ad6628e44f3797327e5ef929bed12011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21541335/?tool=EBIhttps://doaj.org/toc/1932-6203After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression.Antti SiltanenKatsukiyo KitabayashiPäivi LakkistoJohanna MäkeläTommi PätiläMasamichi OnoIlkka TikkanenYoshiki SawaEsko KankuriAri HarjulaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19161 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antti Siltanen Katsukiyo Kitabayashi Päivi Lakkisto Johanna Mäkelä Tommi Pätilä Masamichi Ono Ilkka Tikkanen Yoshiki Sawa Esko Kankuri Ari Harjula hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
description	After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression.
format	article
author	Antti Siltanen Katsukiyo Kitabayashi Päivi Lakkisto Johanna Mäkelä Tommi Pätilä Masamichi Ono Ilkka Tikkanen Yoshiki Sawa Esko Kankuri Ari Harjula
author_facet	Antti Siltanen Katsukiyo Kitabayashi Päivi Lakkisto Johanna Mäkelä Tommi Pätilä Masamichi Ono Ilkka Tikkanen Yoshiki Sawa Esko Kankuri Ari Harjula
author_sort	Antti Siltanen
title	hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
title_short	hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
title_full	hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
title_fullStr	hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
title_full_unstemmed	hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
title_sort	hhgf overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/0c66ad6628e44f3797327e5ef929bed1
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hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.

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