FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil's proatherogenic phenotype which is modulated by semaglutide
Dysfunctional epicardial adiposity is a risk factor for coronary artery disease (CAD). Its genesis is associated with an upregulation of fatty acid binding protein 4 (FABP4) levels, which might exert paracrine inflammatory and atherogenic mechanisms on the cardiovascular system. We aimed to study the prognosis of patients with high systemic FABP4, its association with a neutrophil proatherogenic phenotype, involved mechanisms and its modulation by semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1ra). Higher plasma FABP4 levels than 50 ng/mL were associated with heart failure (HF) onset during follow-up. In patients with CAD, these levels were associated with pro-inflammatory and pro-atherogenic neutrophil profile markers as MPO, NGAL and CD11b, analysed by real-time PCR. The group of patients with the highest FABP4 levels exhibited higher levels of MMP9, CXCR2, and CD11b in neutrophils. A preclinical model, based on neutrophils and coronary endothelial cells, determined the effects of FABP4 on neutrophils' respiratory burst, by flow cytometry, activity of NF-kB, by western blot checking IkBa phosphorylation, CD11b integrin expression levels and adhesion to coronary endothelial cells. A modulation of the neutrophils' transcriptome, analysed by RNA-seq, and plasma chemokine CCL5 levels suggested changes in leukocyte migration and platelet activation pathways in patients who reduced plasma FABP4 levels after semaglutide treatment. Thus, supraphysiological levels of FABP4 induce pro-inflammatory and proatherogenic mechanisms in neutrophils and coronary endothelial cells. Its modulation by semaglutide could explain its benefits on coronary artery disease (CAD). Overall design: Neutrophils (isolated by PolymorphPrep) from patients (n=11) with obesity and cardiovascular disease were isolated before and after semaglutide treatment for 6 months.