Fcγ receptors and ligands and cardiovascular disease

Abstract

Fcγ receptors (FcγRs) classically modulate intracellular signaling on binding of the Fc region of IgG in immune response cells. How FcγR and their ligands affect cardiovascular health and disease has been interrogated recently in both preclinical and clinical studies. The stimulation of activating FcγR in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages causes a variety of cellular responses that may contribute to vascular disease pathogenesis. Stimulation of the lone inhibitory FγcR, FcγRIIB, also has adverse consequences in endothelial cells, antagonizing NO production and reparative mechanisms. In preclinical disease models, activating FcγRs promote atherosclerosis, whereas FcγRIIB is protective, and activating FcγRs also enhance thrombotic and nonthrombotic vascular occlusion. The FcγR ligand C-reactive protein (CRP) has undergone intense study. Although in rodents CRP does not affect atherosclerosis, it causes hypertension and insulin resistance and worsens myocardial infarction. Massive data have accumulated indicating an association between increases in circulating CRP and coronary heart disease in humans. However, Mendelian randomization studies reveal that CRP is not likely a disease mediator. CRP genetics and hypertension warrant further investigation. To date, studies of genetic variants of activating FcγRs are insufficient to implicate the receptors in coronary heart disease pathogenesis in humans. However, a link between FcγRIIB and human hypertension may be emerging. Further knowledge of the vascular biology of FcγR and their ligands will potentially enhance our understanding of cardiovascular disorders, particularly in patients whose greater predisposition for disease is not explained by traditional risk factors, such as individuals with autoimmune disorders.

Keywords: C-reactive protein; atherosclerosis; hypertension; nitric oxide synthase type III.

Figure 1

Effects of Fcγ receptors and their ligands on vascular cells (A) and on preclinical models of cardiometabolic disorders (B). ((Ilustration credit: Ben Smith).

Figure 2

FcγRIIB protein is expressed in human endothelial cells. A–D. FACS was performed in Raji cells (positive control) (A) and in human aortic endothelial cells (HAEC) (B), human coronary artery endothelial cells (C), and human umbilical vein endothelial cells (HUVEC) (D) using 8B5, which is an Alexa Fluor 488-conjugated monoclonal antibody to human FcγRIIB. Findings in the absence of antibody (Ab) and with 8B5 are shown. E. FACS with 8B5 was performed in HAEC transfected with control siRNA (D-001810–02–05, Dharmacon) or siRNA targeting FcγRIIB (GCUACAGGUUCAAGGCCAA, Dharmacon). F. Immunoblotting was performed with 8B5 on plasma membranes isolated from Raji positive control cells and HAEC.

Figure 3

The FcγRIIB-I232 variant has attenuated capacity to mediate CRP action in endothelium. Following siRNA-based knockdown of endogenous FcγRIIB (GAAACCAGCCUCUGAAU, Dharmacon), bovine aortic endothelial cells were transfected with sham plasmid or cDNA encoding human FcγRIIB-T232 or FcγRIIB-I232. A. FcγRIIB abundance was evaluated by immunoblotting, with eNOS detection providing assessment of protein loading. B. CRP (25 ug/ml) antagonism of eNOS activation by VEGF (100 ng/ml) was evaluated by measuring ¹⁴C-L-arginine conversion to ¹⁴C-L-citrulline conversion by intact cells over 15 min. Values are mean±SEM, n=4, *p<0.05 vs no CRP.