The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
The Transforming Growth Factor-β 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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“GDF-15 has also been shown to inhibit apoptosis and inflammation, and protects the heart from injury (36–38).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [38]
Citations
Cites
Free Radicals in the Physiological Control of Cell Function
Dröge, W. (2002) · Physiological Reviews · doi:10.1152/physrev.00018.2001 · Cited by 9,855
Role of Transforming Growth Factor β in Human Disease
Blobe, G. C., Schiemann, W. P., & Lodish, H. F. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005043421807 · Cited by 2,453
Regulation of neuronal survival by the serine-threonine protein kinase Akt
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., & Greenberg, M. E. (1997) · Science · doi:10.1126/science.275.5300.661 · Cited by 2,436
Reperfusion injury induces apoptosis in rabbit cardiomyocytes.
Gottlieb, R. A., Burleson, K. O., Kloner, R. A., Babior, B., & Engler, R. L. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117504 · Cited by 1,442
MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily
Bootcov, M. R., Bauskin, A. R., Valenzuela, S. M., Moore, A. G., Bansal, M., He, X. Y., Zhang, H. P., Donnellan, M., Mahler, S. M., Pryor, K., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11514 · Cited by 1,180
Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress
Sirén, A., Fratelli, M., Brines, M. L., Goemans, C. G., Casagrande, S., Lewczuk, P., Keenan, S., Gleiter, C. H., Pasquali, C., Capobianco, A., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051606598 · Cited by 1,019
Hausenloy, D. J. (2003) · Cardiovascular Research · doi:10.1016/j.cardiores.2003.09.024 · Cited by 1,012
Fujio, Y., Nguyen, T. U., Wencker, D., Kitsis, R. N., & Walsh, K. (2000) · Circulation · doi:10.1161/01.cir.101.6.660 · Cited by 846
Advances in protein kinase B signalling: AKTion on multiple fronts
Brazil, D. P., Yang, Z., & Hemmings, B. A. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.03.006 · Cited by 840
Transgenic Gαq overexpression induces cardiac contractile failure in mice
D’Angelo, D. D., Sakata, Y., Lorenz, J. N., Boivin, G. P., Walsh, R. A., Liggett, S. B., & Dorn, G. W. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.15.8121 · Cited by 629
Research works printed but not linked: 7
- 10.1161/circ.102.8.915 · DOI
- 10.1161/circ.95.1.97 · DOI
- 10.1161/hyp.39.1.87 · DOI
- 10.1161/res.85.9.829 · DOI
- Xu J Kimball TR Lorenz JN Klevitsky R Hewett TE Molkentin JD. GDF-15 functions as a protective and anti-hypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. In press.
- 10.1161/circ.101.6.660 · DOI
- 10.1161/res.88.6.609 · DOI
Cited by
Sorted by citations
Items 601–651 of 651
Gizatulina, T. P., Martyanova, L. U., Petelina, T. I., Зуева, Е. В., & Евгеньевич, Ш. Н. (2021) · Journal of Arrhythmology · doi:10.35336/va-2021-e-32-38
Rhodes, C. J., Abdul‐Salam, V. B., Wharton, J., & Wilkins, M. R. (2011) · CRC Press eBooks · doi:10.1201/b13219-15
Shao, E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809657-4.10948-2
Характеристика основних біомаркерів ішемічного ураження м’язової тканини
Chorna, I., & Motuziuk, O. (2019) · Lesya Ukrainka Eastern European National University Scientific Bulletin Series Biological Sciences · doi:10.29038/2617-4723-2019-387-3-162-172
Mitochondrial Dysfunction and Growth Differentiation Factor 15 in Aging
Fujita, Y., & Tanaka, M. (2022) · Springer eBooks · doi:10.1007/978-981-16-7977-3_9
TGF beta Superfamily Cytokine MIC-1/GDF15 in Health and Inflammatory Diseases
Breit, S. N., & Brown, D. A. (2016) · Encyclopedia of Inflammatory Diseases · doi:10.1007/978-3-0348-0620-6_54-2
Growth Differentiation Factor-15 in Asian IHD Patients
Jang, J. (2023) · JACC Asia · doi:10.1016/j.jacasi.2023.04.004
任, 苏. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.1371699
Ibragimova, R. E., & ZAKHARYAN, E. A. (2023) · Complex Issues of Cardiovascular Diseases · doi:10.17802/2306-1278-2023-12-3-211-219
Dogon, G., Rigal, E., Potel, E., Josse, M., Rochette, L., Béjot, Y., & Vergely, C. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4646293
Ayaz, E., Görkem, Ü., Kan, Ö., Toğrul, C., ŞİMŞEK, Ü., & Han, O. (2024) · Hitit Medical Journal · doi:10.52827/hititmedj.1363447
Greer, C., Chew‐Harris, J., Adamson, P. D., Pemberton, C. J., Pickering, J. W., Pilbrow, A. P., Frampton, C. M., Troughton, R. W., Doughty, R. N., & Richards, M. (2024) · The Journal of Applied Laboratory Medicine · doi:10.1093/jalm/jfae032
Cardiokines and cardiac remodeling
Duttaroy, A. K., & Mallick, R. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-99570-2.00014-x
Chou, T.-Y., Ye, Y.-Z., Lien, C.-J., Wang, J.-C., Yang, C.-H., Chen, Y.-T., Chao, P.-A., & Lin, J.-D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.09.602634
Kuczera, M., Stocerz, K., Sokal, A., Glin, M., Orlińska, K., Siwiec, J., & Olczyk, P. (2024) · Annales Academiae Medicae Silesiensis · doi:10.18794/aams/190929
吴, 婉. (2024) · Advances in Clinical Medicine · doi:10.12677/acm.2024.14112973
Fink, K., Braun, T., Herkel, M., Dürschmied, D., Busch, H.-J., & Helbing, T. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.5063554
Fink, K., Braun, T., Herkel, M., Duerschmied, D., Busch, H.-J., & Helbing, T. (2025) · Research Square · doi:10.21203/rs.3.rs-6810991/v1
Tangeten, C., Bourez, A., Rousseau, A., Imbault, V., Stahl-Zeng, J., Souard, F., Bisteau, X., Delporte, C., Boudjeltia, K. Z., & Antwerpen, P. V. (2025) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2025.130865
Cell therapy for the repair of the mammalian heart
Ang, K. (2013) · Figshare
Wang, Z., Yang, F., Ma, M., Bao, Q., Shen, J., Ye, F., & Xie, X. (2020) · Figshare · doi:10.6084/m9.figshare.13161705
Kosum, P., Siranart, N., Mattanapojanat, N., Phutinart, S., Kongruttanachok, N., Sinphurmsukskul, S., Siwamogsatham, S., Puwanant, S., & Ariyachaipanich, A. (2024) · Figshare · doi:10.6084/m9.figshare.26692474
Relationship Between Growth Differentiation Factor-15 Levels and Micro-Atrial Fibrillation
Orta, H., Aydın, C., Demirkıran, A., Aykaç, H., & Yılmaz, A. (2025) · The European Research Journal · doi:10.18621/eurj.1807849
Ptak, M., Cader-Ptak, A., Marcinowska, Z., Dziedziejko, V., Safranow, K., Kwiatkowska, E., Ciechanowski, K., Pawlik, A., & Domański, L. (2026) · Amino Acids · doi:10.1007/s00726-026-03509-1
Incidences de l’ischémie cérébrale sur la fonction et la sensibilité cardiaques à l’ischémie
Méloux, A. (2019) · theses.fr (ABES) · doi:10.70675/a9b30413z16cbz4038za961z28b244223160
Implication de GDF15 dans la sénescence et les fonctions des cellules endothéliales.
Ha, G. (2019) · theses.fr (ABES) · doi:10.70675/da2fe5b4z744dz47f9z8aadza1047172fb7c
Những tiến bộ trong điều trị suy tim
Lợi, Đ. D., & Hoài, N. T. T. (2018) · Tạp chí Tim Mạch Học Việt Nam · doi:10.58354/jvc.8485.2018.1131
Các biện pháp điều trị trong suy tim tiến triển
Hoài, N. T. T., Hùng, P. M., Cường, T. M., & Hiếu, T. B. (2018) · Tạp chí Tim Mạch Học Việt Nam · doi:10.58354/jvc.8485.2018.1130
Multicellular Cross Talk and Therapeutic Vaccines in Heart Failure
Katoh, M., Nomura, S., Ko, T., Komuro, J., Hayashi, H., Nakagami, H., & Komuro, I. (2026) · Physiology · doi:10.1152/physiol.00007.2026
Iturriaga, T., Margalejo, A., Sal-de-Rellán, A., Iglesias, L. A., Baos, S., Saez‐Maleta, R., Capó, X., González‐Freire, M., Santiago, C., & Pérez-Rivera, J.-Á. (2026) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2026.104804
Tian, N., MeiChun, C., 张松照, Wang, J., Huang, B., Kao, S., Zheng, T., Qin, Y., Zhao, X., Zhang, Z., et al. (2026) · Bioanalysis · doi:10.1080/17576180.2026.2668680
Inflammatory Biomarkers and ECG Repolarization Metrics
Yogasundaram, H., Alemayehu, W. G., Ly, E., deFilippi, C. R., O'Connor, C. M., Temple, T., Sandhu, R. K., Voors, A. A., Westerhout, C. M., & Armstrong, P. W. (2026) · JACC Advances · doi:10.1016/j.jacadv.2026.102922
Adipokine-mediated metabolic responses across BMI in acute myocardial infarction
Sunita, S., Syamsunarno, M. R. A. A., Akbar, M. R., Nugrahani, A. D., Sylviana, N., Nugraha, G. I., Ghozali, M., & Achmad, T. H. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-06140-w
Wu, C., Zhao, Y., & Zhao, Y. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1868998 · Cited by 1
Андреевна, К. Е., Анатольевна, Г. А., Николаевна, В. К., Tukish, O. V., & Kondratiev, M. Y. (2026) · Complex Issues of Cardiovascular Diseases · doi:10.17802/2306-1278-2026-15-3-6-17
Rimolo, L. D. S. M., & Villacorta, H. (2026) · ABC Heart Failure & Cardiomyopathy · doi:10.36660/abchf.20260006i
Rimolo, L. D. S. M., & Villacorta, H. (2026) · ABC Heart Failure & Cardiomyopathy · doi:10.36660/abchf.20260006
Choudhary, D., Bali, S., Bandral, S. S., Singh, V., Ahmad, M. A., Chandrasekaran, B., & Kaur, R. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154408
Lukić, I., Mihić, D., Selthofer-Relatić, K., Arambašić, I., Barbić, J., Mandić, S., Canecki-Varžić, S., & Maričić, L. (2026) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd13080391
Nie, T., 宋红梅, Shen, X., & Mao, L. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1885104
Bonaventura, I., Weigand, I., Isidori, A. M., Kroiß, M., & Reincke, M. (2026) · Endocrine Reviews · doi:10.1210/endrev/bnag035
Szpakowicz, A., Lesiński, W., Tuchliński, J. K., Roszkowska, U., Dubatówka, M., Stachurska, Z., Kondraciuk, M., Rudnicki, W. R., & Kamiński, K. A. (2026) · PLoS ONE · doi:10.1371/journal.pone.0358765
GDF-15 and arrhythmogenesis: From cardiac stress signaling to risk stratification
Chowdhury, D., Garai, S., Pandey, D. P., & Bodakhe, S. H. (2026) · Gene Reports · doi:10.1016/j.genrep.2026.102652
Matwiejuk, M., Myśliwiec, H., Mikłosz, A., Jarocewicz, O., Chabowski, A., & Flisiak, I. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198918
Sridhar, S. M., Renuka, P., Mohan, V. V., Simon, H. A., Bojarajan, N. R. R., & Boominathan, A. (2026) · Indian Journal of Thoracic and Cardiovascular Surgery · doi:10.1007/s12055-026-02280-y
Yoo, H. H. B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27209260
Skeletal Muscle Aging Is a Significant Contributor to Systemic Aging
Li, M.-M., Liu, X., Li, Y., Li, H., Wang, Y., Qiu, K., & Kong, W. (2026) · Biomolecules · doi:10.3390/biom16101527
Metadata
- 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.).
- ORCID
- 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 › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Cardiology and Cardiovascular 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
