Role of SCARF1 in Arterial Inflammation

• Applicants: Dr. Yaw Asare; Professor Dr. Martin Dichgans
• Subject Area: Cardiology, Angiology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519397933

Arterial inflammation manifested as atherosclerosis is the main pathology underlying cardiovascular diseases including myocardial infarction and stroke. Despite the success of lipid-lowering and anti-hypertensive treatment in mitigating the burden of atherosclerotic disease, mortality remains high. A central mechanism driving the development and progression of atherosclerosis is scavenger receptor-mediated uptake of modified lipids by macrophages. This requires both native LDL and oxLDL to cross the endothelial barrier via a mechanism that is not yet fully understood. We and others have shown that genetic variants at SCARF1 associate with the risk of ischemic stroke, particularly large artery atherosclerotic stroke. The majority of variants reside in regulatory DNA. Analysis of expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) suggest that the effects of risk alleles in the SCARF1 gene region on atherogenesis are mediated through elevated SCARF1 expression. However, the suspected link between altered SCARF1 expression and atherosclerosis remains to be established as do the specific mechanisms underlying this relationship. Our working hypothesis is that SCARF1 mediates the transport of LDL/oxLDL across the endothelium and uptake by arterial macrophages to enhance foam cell formation in atherosclerotic lesions. The increase in cholesterol uptake in turn perpetuates cell death mechanisms leading to expansion of the necrotic core. Consequently, Scarf1 deficiency attenuates lipid loading and limits necrotic core and lesion formation - mechanisms that can be targeted for vascular protection. Our preliminary work indicates that Scarf1 deficiency attenuates foam cell formation, atherosclerosis, and necrotic core expansion. Moreover, Scarf1 depletion reduces the uptake of oxLDL in endothelial cells and macrophages. We further established protocol for targeting of therapeutics specifically to atherogenic macrophages. Building on these preliminary data, novel experimental models, and new technology we propose to address the following objectives: 1) detail the effects of global and cell-specific deletion of Scarf1 on atherosclerosis; 2) unravel the molecular role of SCARF1 in cholesterol homeostasis; 3) characterize ApoB100-binding ectodomain region of SCARF1;and 4) analyze the expression and localization of SCARF1 in human atherosclerosis. We expect these findings to provide fundamental insights into the mechanisms underlying human atherosclerosis and open novel therapeutic perspectives.

• DFG Programme: Research Grants