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Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial β-oxidation in cardiomyocytes via activation of the cardiac renin–angiotensin system and induction of miR-208a

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Abstract

Secretory products from epicardial adipose tissue (EAT) from patients with type 2 diabetes (T2D) impair cardiomyocyte function. These changes associate with alterations in miRNA expression, including the induction of miR-208a. Recent studies suggest that activation of the cardiac-specific renin–angiotensin system (RAS) may affect cardiac energy metabolism via induction of miR-208a. This study investigated whether cardiomyocyte dysfunction induced by conditioned media (CM) from EAT-T2D involves activation of the RAS/miR-208a pathway. Therefore, primary adult rat cardiomyocytes were incubated with CM generated from EAT biopsies from patients with T2D and without T2D (ND). Exposing cardiomyocytes to CM-EAT-T2D reduced sarcomere shortening and increased miR-208a expression versus cells exposed to CM-EAT-ND or control medium. The angiotensin II receptor type 1 (AGTR1) antagonist losartan reversed these effects. Accordingly, incubation with angiotensin II (Ang II) reduced sarcomere shortening, and lowered palmitate-induced mitochondrial respiration and carnitine palmitoyltransferase 1c (CPT1c) expression in cardiomyocytes. Locked-nucleic-acid-mediated inhibition of miR-208a function reversed the detrimental effects induced by Ang II. Interestingly, Ang II levels in CM-EAT-T2D were increased by 2.6-fold after culture with cardiomyocytes. The paracrine activation of the cardiac-specific RAS by CM-EAT-T2D was corroborated by increases in the expression of AGTR1 and renin, as well as a reduction in angiotensin-converting enzyme 2 levels. Collectively, these data show that secretory products from EAT-T2D impair cardiomyocyte contractile function and mitochondrial β-oxidation via activation of the cardiac-specific RAS system and induction of miR-208a, and suggest that alterations in the secretory profile of EAT may contribute to the development of diabetes-related heart disease.

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Acknowledgements

This work was financially supported by the German Center for Diabetes Research (DZD), München-Neuherberg, Germany and a Grant to M. Blu. from the German Diabetes Foundation (Grant 367/03/15, entitled “Aktivierung des kardialen Renin-Angiotensin-Systems durch epikardiale Adipokine in Patienten mit Typ 2 Diabetes”).

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Authors and Affiliations

  1. Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    Marcel Blumensatt, Pia Fahlbusch, Rebecca Hilgers, Daniella Herzfeld de Wiza & D. Margriet Ouwens

  2. German Center for Diabetes Research (DZD), München-Neuherberg, Germany

    Marcel Blumensatt, Pia Fahlbusch, Rebecca Hilgers, Daniella Herzfeld de Wiza & D. Margriet Ouwens

  3. Department of Endocrinology, Ghent University Hospital, Ghent, Belgium

    Marlies Bekaert, Johannes B. Ruige & D. Margriet Ouwens

  4. Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany

    Payam Akhyari

  5. Centrum Diabeteszorg, AZ Nikolaas, 9100, Sint-Niklaas, Belgium

    Johannes B. Ruige

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  1. Marcel Blumensatt
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Correspondence to D. Margriet Ouwens.

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Ethical statement

All participants provided written informed consent for the collection of epicardial adipose tissue biopsies during scheduled open heart surgery. The procedures were approved by the local ethical committees of the Heinrich-Heine-University (Duesseldorf, Germany), and Ghent University (Ghent, Belgium) and conducted in accordance with the ethical standards laid down in the Declaration of Helsinki. The animal experiments were performed in accordance with the ‘Principle of laboratory animal care’ (NIH publication No. 85–23, revised 1996) and the current version of the German Law on the protection of animals. The procedures for the isolation of cardiomyocytes were approved by the local ethical committee of the Heinrich-Heine-University (Duesseldorf, Germany).

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The authors declare that they have no conflict of interest.

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Blumensatt, M., Fahlbusch, P., Hilgers, R. et al. Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial β-oxidation in cardiomyocytes via activation of the cardiac renin–angiotensin system and induction of miR-208a. Basic Res Cardiol 112, 2 (2017). https://doi.org/10.1007/s00395-016-0591-0

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