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.

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

“…2D). Also, levels of miR-33a, miR-33b, and miR-208a (miRNAs implicated in fatty acid metabolism [17,18]) were not different between the groups. Activity and expression of the main subunits of PDH were unaltered in the DM group compared with the non-DM group (Fig.…”

Functional characterization of the Ucp1-associated oxidative phenotype of human epicardial adipose tissue

“…Considering that endothelial cell dysfunction is a key aspect of atherosclerosis 56 and adhesion molecules play a central role in the phenomenon 57 , we focused on the relationship between eAT and endothelial cell-activation. That eAT is capable of communicating with cardiomyocytes, endothelial cells and vascular smooth muscle cells has been demonstrated in multiple studies 58 , 59 , this relationship being negative where secretory products from eAT under conditions of diabetes and CAD were used 58 , 59 . In contrast, we observed that sympathetic stimulation of eAT was associated with a shift in its secretion profile that further associated with a downregulation in the expression of adhesion molecules Vcam1 and Icam1 in the human coronary artery endothelial cells.…”

An association study of C9orf3, a novel component of the renin-angiotensin system, and hypertension in diabetes

“…It is well-known that inhibitors of the reninangiotensin system delay the progression of diabetic kidney disease 32,33 . Furthermore, numerous studies have observed activation of the RAS in subjects with type 2 diabetes [34][35][36][37] . RAS and type 2 diabetes are closely related.…”