Abstract 1042: Vascular Adamts7 Promotes Smooth Muscle Foam Cell Formation During Atherosclerosis

Human genetic studies have linked the gene ADAMTS7 with coronary artery disease. In vivo studies in mice demonstrate that ADAMTS7 is proatherogenic, active in smooth muscle cells (SMCs), and induced in response to vascular injury. However, the mechanisms governing its proatherogenicity remain unclear. We generated an SMC specific Adamts7 transgenic mouse (TGSMC) to mimic the induction of vascular ADAMTS7. This mouse was crossed onto the LDL KO background, and after 16 weeks of western diet feeding, TGSMC mice had a 3. 5-fold increase in en-face plaque (p < 0. 01) compared to controls. TGSMC aortas showed a 3-fold increase in foam cells (p = 0. 013) as measured by flow cytometry, and 80% of these cells were SMCs. Subsequent ex vivo studies show increased oxLDL uptake in TGSMC primary SMCs (1. 15x, p < 0. 01). To determine the underlying mechanism, we performed RNA-seq on primary SMCs and found that TGSMCs have increased expression of lipid handling genes (Cd36, Fabp5, Trem2). Upstream regulator analysis identified the transcription factor PU. 1 as a potential mediator of these changes, and siRNA knockdown of PU. 1 attenuated the gene expression increases. Additionally, siRNA knockdown of Cd36, the most upregulated gene, and a known oxLDL receptor, ameliorated the Adamts7-mediated rise in SMC lipid uptake. We next generated an Adamts7 SMC-specific knockout model to test if SMC ADAMTS7 is solely responsible for its proatherogenic effect. Surprisingly, SMC-specific Adamts7 knockout did not affect atherosclerosis in mice. We performed RNAscope on atherosclerotic LDLR KO mice and found that Adamts7 is also expressed in endothelial cells (ECs) during atherogenesis. We bred our hyperlipidemic TG model to the EC-specific Cdh5-CreERT2 and found that EC overexpression of Adamts7 also increases en face plaque burden and foam cell formation (1. 5x, p<0. 05), demonstrating that vascular Adamts7, regardless of the source, increases atherosclerosis. In summary, our results indicate that Adamts7 promotes lipid uptake in vascular SMCs, thus revealing a novel mechanism through which ADAMTS7 mediates atherogenesis. Our findings support the growing body of literature demonstrating that therapeutic targeting of ADAMTS7 is a potential approach to reducing atherosclerosis.