Published online before print January 5, 2006, doi: 10.1161/01.RES.0000202805.73038.48
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© 2006 American Heart Association, Inc.
Molecular Medicine |
The Transforming Growth Factor-ß Superfamily Member Growth-Differentiation Factor-15 Protects the Heart From Ischemia/Reperfusion Injury
From the Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (T.K., M.E., M.N., C.W., J.T., J.H., D.K., H.D., K.C.W.); Department of Neuroanatomy, University of Heidelberg, Germany (J.S.); Division of Molecular Cardiovascular Biology, University of Cincinnati, Ohio (J.X., J.D.M.); and Department of Pathology, University Medical Center, Amsterdam, The Netherlands (H.W.N.).
Correspondence to Priv-Doz Dr Kai C. Wollert, Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str.1, 30625 Hannover, Germany. E-mail wollert.kai{at}mh-hannover.de
Data from the Women’s Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-ß superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO–peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15–deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury.
Key Words: growth-differentiation factor-15 • ischemia/reperfusion • apoptosis • PI3K • Akt
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