The Transforming Growth Factor-beta Superfamily Member Growth-differentiation Factor-15 Protects the Heart from Ischemia/Reperfusion Injury.
From: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Circulation research
- Publish Date: Feb 2006
- ISSN: 1524-4571
- Volume: 98
- Issue: 3
- Pages: 351-60
- Medium: Internet
- Language: English
- Citation (JAMA): Kempf Tibor, Eden Matthias, Strelau Jens, et al. The Transforming Growth Factor-beta Superfamily Member Growth-differentiation Factor-15 Protects the Heart from Ischemia/Reperfusion Injury.. Circ. Res. Feb 2006;98:351-60
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.
Mesh Headings (Keywords): Aged, Animals, Apoptosis, Cells, Cultured, Coronary Vessels, Cytokines, Female, Heart Ventricles, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Muscle Cells, Myocardial Reperfusion Injury, Rats, Rats, Sprague-Dawley, Transforming Growth Factor beta
Check for Full Text / PubMed Unique Identifier (PMID): 16397141
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