Fcγ Receptors and Ligands and Cardiovascular Disease

Fc gamma receptors (Fc gamma Rs) classically modulate intracellular signaling on binding of the Fc region of IgG in immune response cells. How Fc gamma R and their ligands affect cardiovascular health and disease has been interrogated recently in both preclinical and clinical studies. The stimulation of activating Fc gamma R 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 F gamma cR, Fc gamma RIIB, also has adverse consequences in endothelial cells, antagonizing NO production and reparative mechanisms. In preclinical disease models, activating Fc gamma Rs promote atherosclerosis, whereas Fc gamma RIIB is protective, and activating Fc gamma Rs also enhance thrombotic and nonthrombotic vascular occlusion. The Fc gamma R 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 Fc gamma Rs are insufficient to implicate the receptors in coronary heart disease pathogenesis in humans. However, a link between Fc gamma RIIB and human hypertension may be emerging. Further knowledge of the vascular biology of Fc gamma R 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.