Cited by 210Cardiovascular Disease and AdiposityCardiac Fibrosis and RemodelingCardiovascular Function and Risk Factors

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Secretory Products From Epicardial Adipose Tissue of Patients With Type 2 Diabetes Mellitus Induce Cardiomyocyte Dysfunction

Greulich, Sabrina, Maxhera, Bujar, Vandenplas, Guy, de Wiza, Daniella Herzfeld, Smiris, Konstantinos, Mueller, Heidi, Heinrichs, Jessica, Blumensatt, Marcel, Cuvelier, Claude, Akhyari, Payam, Ruige, Johannes B., Ouwens, D. Margriet, Eckel, Juergen·2012·Circulation

DOI 10.1161/circulationaha.111.039586

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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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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
ORCID: Akhyari, Payam
Ouwens, D. Margriet
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2012-11-06
Volume: 126
Issue: 19
Pages: 2324-2334
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.111.039586
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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Secretory Products From Epicardial Adipose Tissue of Patients With Type 2 Diabetes Mellitus Induce Cardiomyocyte Dysfunction

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