Genetic Modifiers of Atherosclerosis: Understanding and Targeting the Mechanism of the ApoER2-R952Q Mutation - PROJECT SUMMARY The scientific understanding of blood vessels has evolved significantly over the decades. They are now recognized as active gatekeepers that control organ function rather than passive conduits responding to external cues. Endothelial dysfunction is implicated in various pathologies, including atherosclerosis, which is a progressive disease linked to aging, hypertension, diabetes, and dyslipidemia. This condition involves subendothelial inflammation, arterial remodeling, lipid and cholesterol accumulation, arterial stiffness, and lumenal obstruction, which can lead to thrombosis, myocardial infarction, and stroke. Despite preventive therapies like statins, atherosclerosis remains a leading cause of death worldwide. The apolipoprotein E receptor-2 (ApoER2), encoded by the LRP8 gene, is expressed in endothelial cells and is a significant genetic modifier for premature atherosclerosis and acute myocardial infarction, identified across various human populations. Homozygous carriers of the ApoER2-R952Q variant have a twofold increased risk for cardiovascular disease, and those with the ApoE4 variant show a 3.9-fold increased susceptibility. This single-nucleotide polymorphism (SNP) R952Q is thought to confer a gain of function to ApoER2, although the mechanism remains unclear. In addition to ApoE, ApoER2 also binds to Reelin, an extracellular protein that is abundant in the blood. We have shown on endothelial cells that Reelin / ApoER2 interaction promotes vascular adhesion and leukocyte infiltration by elevating vascular immune surveillance. In the atherosclerosis-prone LDLR-deficient (Ldlr-/-) mouse model, Reelin depletion reduces leukocyte-endothelial adhesion and expression of pro-inflammatory adhesion molecules VCAM-1 and ICAM-1, slowing atherosclerosis progression and decreasing macrophage content in lesions. In human endothelial cells, Reelin / ApoER2 signaling enhances monocyte adhesion and upregulates ICAM1, VCAM1, and E-selectin by activating the nuclear factor κB (NF-κB). Based on these findings, we hypothesize that the ApoER2-R952Q mutation increases endothelial adhesion and leukocyte permeability, promoting endothelial dysfunction, inflammation, and plaque formation, which leads to atherosclerosis. To test this hypothesis, we have developed a mouse model with the equivalent Apoer2- R859Q mutation and propose here to dissect this mechanism leading to increased cardiovascular disease risk.
