title: 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.
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.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Blumensatt
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Fahlbusch
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hilgers
authors.affiliation: Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Marlies
authors.initials: M
authors.lastname: Bekaert
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Daniella
authors.initials: D
authors.lastname: Herzfeld de Wiza
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Payam
authors.initials: P
authors.lastname: Akhyari
authors.affiliation: Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.|Centrum Diabeteszorg, AZ Nikolaas, 9100, Sint-Niklaas, Belgium.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Ruige
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany. margriet.ouwens@ddz.uni-duesseldorf.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany. margriet.ouwens@ddz.uni-duesseldorf.de.|Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. margriet.ouwens@ddz.uni-duesseldorf.de.
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000503:physiopathology*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010496:Pericardium / Q000166:cytology; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D059467:Transcriptome
chemical_list: D017077:Culture Media, Conditioned; C569395:MIRN208 microRNA, rat; D035683:MicroRNAs
keywords: Angiotensin II; Cardiomyocytes; Contractile function; Epicardial adipose tissue; MiR-208a; Mitochondrial function