Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 68, Issue -, Pages 56-65Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2014.01.005
Keywords
Growth factors; Cytokines; Ischemia-reperfusion injury; Hypoxia; Fibroblasts; Cardiomyocytes
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Agence de Biomedecine
- Ministere de l'Enseignement Superieur et de la Recherche, France
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Roles of cardiac fibroblasts (CFs) in the regulation of myocardial structure and function have been emphasized in the last decade. Their implications in pathophysiological aspects of chronic heart diseases such as myocardial remodeling and fibrosis are now well established; however their contribution to the acute phase of ischemia-reperfusion injury still remains elusive. We hypothesized that CF may contribute to cardiomyocyte (CM) protection against ischemia-reperfusion injuries. Experiments performed on isolated neonatal rat CF and CM demonstrated that the presence of CF in co-cultures increases CM viability (58 +/- 2% versus 30 +/- 2% in control) against hypoxia-reoxygenation injury, in a paracrine manner. It was confirmed by a similar effect of hypoxic CF secretome alone on CM viability (51 +/- 9% versus 31 +/- 4% in untreated cells). These findings were corroborated by in vivo experiments in a mice model of myocardial infarction in which a 25% infarct size reduction was observed in CF secretome treated mice compared to control. Tissue inhibitor of metalloproteinases-1 (TIMPs-1) alone, abundantly detected in CF secretome, was able to decrease CM cell death (35%) and experiments with pharmacological inhibitors of PI3K/Akt and ERK1/2 pathways provided more evidence that this paracrine protection is partly mediated by these signaling pathways. In vivo experiments strengthened that TIMP-1 alone was able to decrease infarct size (37%) and were validated by depletion experiments demonstrating that CF secretome cardioprotection was abolished by TIMP-1 depletion. Our data demonstrated for the first time that CFs participate in cardioprotection during the acute phase of ischemia-reperfusion via a paracrine pathway involving TIMP-1. (C) 2014 Elsevier Ltd. All rights reserved.
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