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.
Highlights
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- superfamily, are an independent risk indicator for adverse cardiovascular events
We found GDF-15 to be strongly induced in the infarcted murine myocardium and in left ventricular (LV) tissue samples obtained from patients who had died after an acute myocardial infarction (AMI)
Identification of GDF-15 as an NO-Regulated Gene in Cardiomyocytes Expanding on our previous efforts to identify NO-regulated genes in cardiomyocytes that are functionally important,[15,16] we performed cDNA expression array analyses in cardiomyocytes cultured for 24 hours in the presence or absence of the NO donor SNAP (250 mol/L)
Summary
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- superfamily, are an independent risk indicator for adverse cardiovascular events. GDF-15 mRNA and pro-peptide expression levels were induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO–peroxynitrite-dependent signaling pathways. Data from the Women’s Health Study show that GDF-15 serum levels are an independent risk indicator for adverse cardiovascular events, including stroke and AMI.[11] 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 massively upregulated by nitrosative stress in cardiomyocytes subjected to simulated I/R. Recombinant GDF-15 protects cardiomyocytes from ischemic injury via phosphoinositide 3-OH kinase (PI3K) and Akt-dependent signaling pathways. Our results identify GDF-15 as a novel cardioprotective cytokine
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