Factor H-related protein 1 (FHR-1) is associated with atherosclerotic cardiovascular disease

Abstract

Atherosclerotic cardiovascular disease (ACVD) is a lipid-driven inflammatory disease and one of the leading causes of death worldwide. Lipid deposits in the arterial wall lead to the formation of plaques that involve lipid oxidation, cellular necrosis, and complement activation, resulting in inflammation and thrombosis. The present study found that homozygous deletion of the CFHR1 gene, which encodes the plasma complement protein factor H-related protein 1 (FHR-1), was protective in two cohorts of patients with ACVD, suggesting that FHR-1 accelerates inflammation and exacerbates the disease. To test this hypothesis, FHR-1 was isolated from human plasma and was found to circulate on extracellular vesicles and to be deposited in atherosclerotic plaques. Surface-bound FHR-1 induced the expression of pro-inflammatory cytokines and tissue factor in both monocytes and neutrophils. Notably, plasma concentrations of FHR-1, but not of factor H, were significantly (p < 0.001) elevated in patients with ACVD, and correlated with the expression of the inflammation markers C-reactive protein, apolipoprotein serum amyloid protein A, and neopterin. FHR-1 expression also significantly correlated with plasma concentrations of low-density lipoprotein (LDL) (p < 0.0001) but not high-density lipoprotein (HDL). Taken together, these findings suggest that FHR-1 is associated with ACVD.

Identification of CFHR4 as a Potential Prognosis Biomarker Associated With lmmune Infiltrates in Hepatocellular Carcinoma

“…For example, CFHR1 exacerbates atherosclerotic cardiovascular disease by altering the expression levels of C-reactive protein apolipoprotein and serum amyloid protein A (30). All CFHR genes are genetic risk factors for AMD (31).…”

“…Members of the CFHR family of proteins play key roles in the progression of multiple diseases through multiple mechanisms. For example, CFHR1 exacerbates atherosclerotic cardiovascular disease by altering the expression levels of C-reactive protein apolipoprotein and serum amyloid protein A ( 30 ). All CFHR genes are genetic risk factors for AMD ( 31 ).…”

The multifaceted impact of complement on atherosclerosis

“…Notably, in a large cohort study of FH patients, the Y402H variant showed a two-fold decrease in susceptibility to CVD, which became consistently stronger when stratifying by earlier age of onset [114]. Homozygous deletion of the CFHR1 gene, which has a protective role in AMD, has been recently reported to associated with a lower risk for atherosclerotic cardiovascular disease in two independent cohorts [115]. In the same study, levels of CFHR1, but not CFH, were found to be significantly heightened in CVD patients and to correlate with markers of inflammation [115].…”

“…Homozygous deletion of the CFHR1 gene, which has a protective role in AMD, has been recently reported to associated with a lower risk for atherosclerotic cardiovascular disease in two independent cohorts [115]. In the same study, levels of CFHR1, but not CFH, were found to be significantly heightened in CVD patients and to correlate with markers of inflammation [115]. This might be in part due to the preferential binding of CFHR1 to MDA epitopes that prevents CFH from exerting its complement-regulatory effects on MDA-decorated apoptotic/necrotic cell surfaces [116].…”

The OSE complotype and its clinical potential

“…Although CFH does not directly interact with 4-HNE-epitopes, it protects ARPE-19 cells from 4-HNE-induced cell death by attenuating apoptotic and necroptotic cell death pathways (52,109). Next to OSEs, CFH binds many other DAMPs on the surface of dying cells, apoptotic blebs, and MVs (52,110,127,128). There, CFH compensates for the loss of membrane-bound complement inhibitors by protecting cells from excessive complement activation and limiting inflammatory potential (127,128).…”