Cardiac fibroblasts protect cardiomyocytes against lethal ischemia-reperfusion injury.
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.
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France. Electronic address: maryline.abrial@univ-lyon1.fr.
Maryline
M
Abrial
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France.
Claire Crola
CC
Da Silva
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France.
Bruno
B
Pillot
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France.
Lionel
L
Augeul
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France; Université François Rabelais EA 4245, CHRU Tours, Hôpital Trousseau, Service de Cardiologie, F-37044 Tours, France.
Fabrice
F
Ivanes
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France.
Geoffrey
G
Teixeira
Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles Cardiovasculaires & CIC de Lyon, F-69394 Lyon, France.
Régine
R
Cartier
Université François Rabelais EA 4245, CHRU Tours, Hôpital Trousseau, Service de Cardiologie, F-37044 Tours, France.
Denis
D
Angoulvant
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France; Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles Cardiovasculaires & CIC de Lyon, F-69394 Lyon, France.
Michel
M
Ovize
INSERM U1060, CarMeN Laboratory, Université Lyon 1, F-69373 Lyon, France.
René
R
Ferrera
D000818:Animals; D002470:Cell Survival; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism* / Q000502:physiology; D006352:Heart Ventricles / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D058628:Myofibroblasts / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology
D017077:Culture Media, Conditioned; D016207:Cytokines; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1
Cardiomyocytes; Cytokines; Fibroblasts; Growth factors; Hypoxia; Ischemia–reperfusion injury