Cited by 651GDF15 and Related BiomarkersCardiac Ischemia and ReperfusionCardiac Fibrosis and Remodeling

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

Kempf, Tibor, Eden, Matthias, Strelau, Jens, Naguib, Marian, Willenbockel, Christian, Tongers, Jörn, Heineke, Jörg, Kotlarz, Daniel +5 more·2006·Circulation Research

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.

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Crossref · 10.1161/01.res.0000202805.73038.48

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Authors
Kempf, T., Eden, M., Strelau, J., Naguib, M., Willenbockel, C., Tongers, J., Heineke, J., Kotlarz, D., Xu, J., Molkentin, J. D., Niessen, H. W., Drexler, H., & Wollert, K. C.
Affiliations
  • Heidelberg University (DE)
  • 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.).
Venue
Circulation Research
Published
2006-02-17
Volume
98
Issue
3
Pages
351-360
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2130073289
Cited by
651
References
44
Citations by year
2026: 26 · 2025: 37 · 2024: 38 · 2023: 32 · 2022: 32 · 2021: 44 · 2020: 54 · 2019: 53 · 2018: 36 · 2017: 32 · 2016: 36 · 2015: 27 · 2014: 34 · 2013: 34 · 2012: 27
FWCI
9.90
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Medizinischen Hochschule Hannover
Topics
  • Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
growth differentiation factor 15, GDF15, myocardial ischemia-reperfusion injury, cardioprotection, cardiomyocyte apoptosis, nitrosative stress, phosphatidylinositol 3-kinase/Akt signaling, acute myocardial infarction
MeSH terms
Aged, Animals, Cells, Cultured, Coronary Vessels, Female, Heart Ventricles, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Myocardial Reperfusion Injury, Cytokines, Transforming Growth Factor beta, Ventricular Function, Rats, Sprague-Dawley, Apoptosis, Mice, Knockout, Muscle Cells, Mice, Rats, Growth Differentiation Factor 15

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