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

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.

Epicardial adipose tissue: at the heart of the obesity complications

“…In fact, in line with other fat depots [56,57], not only extracellular matrix proteins are remarkably increased in EAT in cardiac pathological conditions [58], but EAT may also induce fibrosis in the neighboring myocardium through the secretion of profibrotic mediators including inflammatory cytokines, growth factors and matrix metalloproteinases [59,60] (Fig. 1).…”

“…Of note, activin A concentration in the EAT secretome is highly variable, with higher levels in predisposing conditions for atrial arrhythmias, such as heart failure [59], obesity and type 2 diabetes [60]. Of note, type 2 diabetes-induced alterations in the secretory profile of EAT have been even overall associated with the development of insulin resistance and negative inotropic effects in rat cardiomyocytes, suggesting that in type 2 diabetes EAT could also locally contribute to the pathogenesis of cardiomyopathy [60].…”

“…After all, EAT is a source of inflammatory cytokines and reactive oxygen species, known to be associated with a high incidence of atrial fibrillation, as well as of adipokines involved in calcium homeostasis of cardiomyocytes and, therefore, in the electrical properties of the atria [60].…”

Fat and Lipid Partitioning: Phenotyping Beyond BMI

“…It has also been reported an association between EAT volume and atrial fibrillation independent of common atrial fibrillation risk factors and obesity [56]. In this regard, EAT might promote fibrosis in the neighbouring myocardium through the secretion of profibrotic factors including inflammatory cytokines, growth factors and matrix metalloproteinases [49,57]. When atrial myocardium was incubated with the secretome of EAT, but not of parasternal SC fat, obtained from CAD patients in an ex vivo model, it developed NorCal Open Access Publications .…”

Thermogenic potential and physiological relevance of human epicardial adipose tissue

“…52 In addition to the studies looking at gene expression of the inflammatory and oxidative stress markers, proteomic and secretome analyses of epicardial fat obtained from CAD patients have also revealed that it is capable of secreting factors that can induce atherogenic changes in monocytes and endothelial cells, 53 as well as induce cardiomyocyte dysfunction. 54 Conditioned media derived from epicardial fat of guinea pigs was also reported to induce insulin resistance in rat cardiomyocytes. 55 These observations tend to support the 'outside to inside' signaling hypothesis, which suggests that secretory products of dysfunctional epicardial fat or adventitia can lead to the development of intimal atherosclerotic lesions in coronary arteries and other blood vessels.…”