The Transforming Growth Factor-β Superfamily Member Growth-Differentiation Factor-15 Protects the Heart From Ischemia/Reperfusion Injury

• Published in: Circulation research Vol. 98; no. 3; pp. 351 - 360
• Main Authors: Kempf, Tibor, Eden, Matthias, Strelau, Jens, Naguib, Marian, Willenbockel, Christian, Tongers, Jörn, Heineke, Jörg, Kotlarz, Daniel, Xu, Jian, Molkentin, Jeffery D, Niessen, Hans W, Drexler, Helmut, Wollert, Kai C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 17.02.2006; Lippincott
• Subjects: Aged; Animals; Apoptosis; Biological and medical sciences; Cells, Cultured; Coronary Vessels - physiology; Cytokines - deficiency; Cytokines - genetics; Cytokines - physiology; Female; Fundamental and applied biological sciences. Psychology; Growth Differentiation Factor 15; Heart Ventricles - cytology; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Middle Aged; Muscle Cells - physiology; Myocardial Reperfusion Injury - prevention & control; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta - physiology; Ventricular Function; Vertebrates: cardiovascular system; Heart; Transforming growth factor β; Ischemia reperfusion; Akt; ischemia/reperfusion; Vertebrata; Mammalia; PI3K; growth-differentiation factor-15; Circulatory system; Differentiation; Apoptosis; Growth factor
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000202805.73038.48

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-β 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.