Apolipoprotein J protects cardiomyocytes from lipid-mediated inflammation and cytotoxicity induced by the epicardial adipose tissue of diabetic patients

Abstract

Apolipoprotein J; Epicardial adipose tissue; Type 2 diabetes

Apolipoprotein J; Teixit adipós epicàrdic; Diabetis tipus 2

Apolipoproteína J; Tejido adiposo epicárdico; Diabetes tipo 2

Diabetic patients present increased volume and functional alterations in epicardial adipose tissue (EAT). We aimed to analyze EAT from type 2 diabetic patients and the inflammatory and cytotoxic effects induced on cardiomyocytes. Furthermore, we analyzed the cardioprotective role of apolipoprotein J (apoJ). EAT explants were obtained from nondiabetic patients (ND), diabetic patients without coronary disease (DM), and DM patients with coronary disease (DM-C) after heart surgery. Morphological characteristics and gene expression were evaluated. Explants were cultured for 24 h and the content of nonesterified fatty acids (NEFA) and sphingolipid species in secretomes was evaluated by lipidomic analysis. Afterwards, secretomes were added to AC16 human cardiomyocytes for 24 h in the presence or absence of cardioprotective molecules (apoJ and HDL). Cytokine release and apoptosis/necrosis were assessed by ELISA and flow cytometry. The EAT from the diabetic samples showed altered expression of genes related to lipid accumulation, insulin resistance, and inflammation. The secretomes from the DM samples presented an increased ratio of pro/antiatherogenic ceramide (Cer) species, while those from DM-C contained the highest concentration of saturated NEFA. DM and DM-C secretomes promoted inflammation and cytotoxicity on AC16 cardiomyocytes. Exogenous Cer16:0, Cer24:1, and palmitic acid reproduced deleterious effects in AC16 cells. These effects were attenuated by exogenous apoJ. Diabetic secretomes promoted inflammation and cytotoxicity in cardiomyocytes. This effect was exacerbated in the secretomes of the DM-C samples. The increased content of specific NEFA and ceramide species seems to play a key role in inducing such deleterious effects, which are attenuated by apoJ.

This research was funded by grants FIS PI16/00471 and PI20/00334 from the Instituto de Salud Carlos III (co-financed by the European Regional Development Fund). N.P is funded by the Instituto de Salud Carlos III predoctoral contract FI20/00252. A.P.P., S.B., and JLS-Q are members of CIBER of Diabetes and Metabolic Diseases (CIBERDEM, CB07/08/0016, Instituto de Salud Carlos III Project). S.B, J.L.S.-Q, and N.P are members of the Quality Research Group 2017-SGR-1149 from Generalitat de Catalunya, and of the Spanish Atherosclerosis Society Vascular Biology Group. Institut de Recerca Sant Pau (IR Sant Pau) is accredited by CERCA Program/Generalitat de Catalunya.