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Secretory Products From Epicardial Adipose Tissue of Patients With Type 2 Diabetes Mellitus Induce Cardiomyocyte Dysfunction
Abstract
BACKGROUND: Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes. METHODS AND RESULTS: Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a. CONCLUSIONS: Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.
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“Such a scenario is strongly suggested by the study of Greulich et al. indicating that cardiomyocytes of rat incubated with conditioned media generated from explants of EAT biopsies performed in T2DM patients became dysfunctional and insulin resistant [92].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [92]
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“The study also demonstrated that the secretion pattern of EAT was considerably different from SAT and PAT, and in diabetic compared to non-diabetic individuals.”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [92]
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Metadata
- Authors
- Greulich, S., Maxhera, B., Vandenplas, G., de Wiza, D. H., Smiris, K., Mueller, H., Heinrichs, J., Blumensatt, M., Cuvelier, C., Akhyari, P., Ruige, J. B., Ouwens, D. M., & Eckel, J.
- Affiliations
- Deutsches Diabetes-Zentrum e.V. (DE)
- From the Institute of Clinical Biochemistry and Pathobiochemistry (S.G., D.H.d.W., H.M., J.H., M.B., D.M.O.) and Paul Langerhans Group – Integrative Physiology (J.E.), German Diabetes Center, Duesseldorf, Germany; the Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (B.M., K.S., P.A.); and the Heart Centre (G.V.), the Department of Pathology (C.C.), and the Department of Endocrinology (J.B.R., D.M.O.), Ghent University Hospital, Ghent...
- Corresponding author
- Ouwens, D. Margriet
- Venue
- Circulation
- Published
- 2012-11-06
- Volume
- 126
- Issue
- 19
- Pages
- 2324-2334
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2049514014
- Cited by
- 210
- References
- 45
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 16 · 2023: 15 · 2022: 22 · 2021: 19 · 2020: 13 · 2019: 18 · 2018: 13 · 2017: 18 · 2016: 14 · 2015: 6 · 2014: 10 · 2013: 15
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- epicardial adipose tissue, type 2 diabetes, cardiomyocyte dysfunction, cardiac contractile function, insulin action, activin A, angiopoietin-2, CD14, Smad2 phosphorylation, SERCA2a, calcium handling, conditioned medium, diabetic cardiomyopathy
- MeSH terms
- Adipose Tissue, Aged, Animals, Biopsy, Calcium, Cells, Cultured, Diabetes Mellitus, Type 2, Humans, Insulin, Male, Pericardium, Rats, Inbred Lew, Sarcomeres, Signal Transduction, Culture Media, Conditioned, Models, Animal, Activins, Myocytes, Cardiac, Angiopoietin-2, Rats, Sarcoplasmic Reticulum Calcium-Transporting ATPases
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