Secretory Products from Epicardial Adipose Tissue of Patients with Type 2 Diabetes Induce Cardiomyocyte Dysfunction
Background—Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study was aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes (DM2) affect contractile function and insulin action in cardiomyocytes.
Methods and Results—Contractile function and insulin action was analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without (ND) and with DM2. CM from subcutaneous (SAT) and pericardial adipose tissue (PAT) biopsies from the same patients served as control. Cardiomyocytes treated with CM (EAT) from DM2-patients showed reductions in sarcomere shortening, cytosolic Ca2+-fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a (SERCA2a), and decreased insulin-mediated Akt-Ser473-phosphorylation as compared to 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-ND 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 SERCA2a.
Conclusions—Collectively, our data implicate DM2-related alterations in the secretory profile of EAT, in the pathogenesis of diabetes-related heart disease.
- Received April 27, 2011.
- Accepted October 1, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited