Deletion of the mouse homolog of human FHR1 (FHRE) protects ApoE-/- mice from atherosclerosis

Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, subsequent infiltration by monocytes/macrophages, and development of inflammation. Macrophage-driven inflammation causes oxidative stress, thereby enhancing endothelial cell activation, immune cell recruitment, and foam cell formation. Lowering LDL plasma levels, as well as inhibiting inflammation, reduces the risk of cardiovascular events. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation driven by monocytes/macrophages and neutrophilic granulocytes. Moreover, the concentration of FHR1 is higher, whereas CFHR1 gene deletion frequency is significantly lower, in patients with atherosclerosis than in healthy controls. To investigate the link between FHR1 and atherosclerosis, we generated FHRE-/- (the murine homolog of FHR1) knockout mice and then crossed them with ApoE-/- knockout mice (a model of human atherosclerosis). Notably, deletion of FHRE enhanced lipid degradation in liver as seen by RNAseq analysis, resulting in normalized cholesterol levels, reduced inflammation and no plaque formation in FHRE-/-ApoE-/- mice than in ApoE-/- mice expressing FHRE. These data indicate that FHRE directs uptake of oxLDL by macrophages, and supports foam cell formation, plaque development, and inflammation in dislipidemic mice. As human FHR1 correlates with non-HDL cholesterol concentrations and inflammation markers in patients with atherosclerosis-associated cardiovascular disease (ACVD) we assume that FHR1/FHRE plays a key role in development of atherosclerosis and subsequent events such as stroke and heart attack.