EXPRESSION OF DE NOVO CERAMIDE SYNTHESIS IN LOCAL HEART FAT DEPO IN PATIENTS WITH CARDIOVASCULAR DISEASES

Abstract

Introduction. Ceramides are bioactive lipids that are not only structural components of cell membranes, but also second messengers in the transmission of cell signals. Ceramides are associated with risk factors for cardiovascular disease, may be independent predictors of cardiovascular events and proatherogenic mediators. However, due attention has not been paid to the problem of ceramide accumulation in the adipose tissue (AT) of the heart, while the accumulation of ceramides in adipocytes of epicardial and perivascular AT in coronary heart disease (CHD) is of particular interest, since they are localized in close proximity to the coronary vessels and the focus of the lesion.Objective: to evaluate the expression of de novo ceramide biosynthesis enzymes in the adipose tissue of the heart of various locations in patients with coronary heart disease and acquired heart defects.Materials and methods. The study included 30 patients with CAD, the comparison group consisted of 30 patients with acquired valvular disease (aortic stenosis/insufficiency) without CAD. During the operation, biopsies of subcutaneous, epicardial, perivascular adipose tissue (VT) (SAT, EAT, PVAT, respectively) were obtained. Expression of genes encoding de novo ceramide synthesis enzymes (subunits of C1 and C2 serine palmitoyltransferases: SPTLC1, SPTLC2; ceramide synthase 1-6: CERS1-6; dihydroceramide desaturase: DEGS1) was assessed by real-time quantitative polymerase chain reaction (qPCR) with primers synthesized by Evrogen (Moscow, Russia) on the ViiA 7 Real-Time PCR System (Applied Biosystems, Foster City, California, USA). Statistical analysis of the results was performed using GraphPad Prism 8 (GraphPad Software).Results. Patients with CAD were characterized by higher levels of SPTLC1 mRNA in subcutaneous and epicardial VT and SPTLC2 mRNA in EAT. DEGS1 expression was maximal in SVT and EAT. The expression of ceramide synthase genes in VT of patients with coronary artery disease had tissue-specific features. Expression of the CERS1 gene, encoding the enzyme ceramide synthase-1, which produces ceramides with a fatty acid residue in its composition of 18 carbon atoms (C18), expression of CERS5 and CERS6, encoding ceramide synthase-5 and -6, synthesizing ceramides C14-C16 was maximum in epicardial adipocytes. At the same time, CERS5 expression was higher than CERS6 expression. Gene expression of CERS2, encoding the enzyme ceramide synthase-2, which produces long-chain ceramides and attaches C20–C24 fatty acyl-CoA to the sphingoid base in ceramide, was maximal in subcutaneous adipocytes. While perivascular VT was characterized by a higher expression of the CERS4 and CERS3 genes, which synthesize very long chain ceramides C26 and higher. In the group of patients with valvular disease, VT samples did not differ in terms of SPTLC1, SPTLC2, CERS1, CERS2, CERS5, and CERS6 mRNA levels. However, high expression of CERS4 and DEGS1 was observed in EAT, while CERS3 and CERS4 were expressed in PVAT. When comparing the level of expression of genes for ceramide synthesis enzymes between the two studied groups, it was found that in patients with IHD, the mRNA level of SPTLC1 in SAT and EAT, SPTLC2 in EAT, CERS2 in all types of AT, CERS4 and CERS5 in EAT, DEGS1 in SAT and EAT was higher in compared with patients with valvular heart disease.Conclusion. Regional fat depots of the heart differed in the level of expression of de novo ceramide biosynthesis enzymes. The results obtained indicate the activation of ceramide synthesis along this pathway in adipocytes of predominantly epicardial localization in coronarogenic pathology, which may contribute to the accumulation of long-chain ceramides in the VT of this localization.

Keywords

• церамиды
• жировая ткань сердца
• ишемическая болезнь сердца
• приобретенные пороки сердца