title: The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury.
abstract: 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-beta 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.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Matthias
authors.initials: M
authors.lastname: Eden
authors.forename: Jens
authors.initials: J
authors.lastname: Strelau
authors.forename: Marian
authors.initials: M
authors.lastname: Naguib
authors.forename: Christian
authors.initials: C
authors.lastname: Willenbockel
authors.forename: Jörn
authors.initials: J
authors.lastname: Tongers
authors.forename: Jörg
authors.initials: J
authors.lastname: Heineke
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Hans W
authors.initials: HW
authors.lastname: Niessen
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D055436:Growth Differentiation Factor 15; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D032342:Muscle Cells / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000502:physiology*; D016276:Ventricular Function
chemical_list: D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta