Semaglutide effects on human epicardial and subcutaneous fat released exosomes, aortic endothelial cells and neutrophils

Abstract

Abstract Background Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients have cardiovascular disease (CVD) and obese patients have a 95% risk of heart failure (HF) and, consequently, of death. The proinflammatory profile of epicardial fat (EAT) participates in this pathological mechanism. New drugs based on GLP-1 receptor agonists (GLP-1-RA) have demonstrated benefits on CVD. Semaglutide is a new GLP-1-RA that can reduce body weight and atherogenesis process. Purpose To study the semaglutide effects on human epicardial fat, aortic endothelial cells and neutrophils as main involved-cardiovascular cells on atherogenesis. Materials and Methods Epicardial (EAT) and subcutaneous fat (SAT) biopsies were collected from patients undergoing open-heart surgery. All the patients signed an informed consent. Differential fat-released exosomes, isolated by Exo-Spin Exosome Purification Kit, regarding semaglutide or/and insulin treatment were characterized by proteomics Triple TOF (n=3). Modulation of human neutrophils (dHL60 cells) phenotype, obtained after promyelocytic cell differentiation, and adhesion into human aortic endothelial cells (HAEC) by Semaglutide were analyzed by flow cytometry and functional analysis, respectively. Semaglutide effects on angiogenesis were performed on HAEC according to the manufacturer’s protocol. GLP-1 receptor expression levels were confirmed by real time-PCR. Results Fat biopsies, neutrophils and HAEC expressed GLP-1 receptor, measured by qPCR. We did not observe differential exosomes-cargo after semaglutide treatment on EAT. However, the released-exosomes from SAT with ANXA5, FABP4, GSN, SERPINF1 and PRDX1 were modulated by Semaglutide treatment. In addition, the CD11b molecule expression on neutrophils (p=0.0482) and their adhesion (p=0.0148) into HAEC treated with high glucose (22.2 mM) were modulated by Semaglutide treatment. Finally, GLP-1-RA improves angiogenesis, measured by loop formation after 20 hours. Conclusion Semaglutide modulates the released exosomes by SAT, the neutrophils adhesion into endothelial cells and enhances the angiogenesis process. These results suggest a new anti-inflammatory and anti-atherogenic role of this molecule in the human cardiovascular cell system.Figure 1Figure 2