Abstract 18666: SR-BI and Tyrosine Kinase Inhibitors: A Novel Pathway for Atherosclerotic Cardiovascular Disease Therapeutic Development

Abstract

Introduction: Cardiovascular disease (CVD) is the leading cause of death in the U.S., where coronary artery disease (CAD) accounts for 42.1% of all CVD deaths. Current therapeutics focus on lowering LDL-C, as previous attempts to raise HDL-C were not successful in altering CVD outcomes. However, the therapeutic potential of HDL has not been fully explored. Variants in SCARB1, the gene that encodes HDL receptor Scavenger Receptor B1 (SR-BI), are associated with dyslipidemia and atherosclerotic CVD (ASCVD), and we first to identified Mendelian inheritance of SCARB1 variants that cause severe early-onset CAD and dyslipidemia. Limited clinical evidence suggests imatinib reduces total cholesterol in chronic myeloid leukemia (CML). Additionally, TKI treatment in atherosclerotic mice reduced total cholesterol (imatinib) and atherosclerotic lesions (dasatinib). Yet, no data is available on the effects of TKIs on HDL and RCT. Hypothesis: Our findings suggest that HDL function (vs. HDL-C concentration) in reverse cholesterol transport (RCT) may be a promising target for cholesterol-based therapy and studying TKIs in RCT may provide a novel mechanism for therapeutic development. Methods: We performed a high throughput drug screen with 788 FDA-approved compounds, using HepG2 cells to measure endogenous HDL binding. We identified four compounds that significantly increased HDL binding, of which, imatinib was the only one to increase SR-BI. Wildtype C57Bl/6 mice on a high fat, high cholesterol diet, underwent imatinib treatment for 4 weeks and measured biweekly serum lipids. Results: We have found that imatinib and dasatinib significantly enhance HDL binding, where imatinib increased SR-BI, ABCA1, and ABCG1 in vitro. Furthermore, in vivo imatinib treatment decreased plasma total cholesterol, HDL-C and triglyceride levels, and elevated hepatic SR-BI. Knockdown of SR-BI in HepG2 cells ameliorated the imatinib-induced HDL binding increase suggesting an SR-BI-specific mechanism. Mass spectrometry revealed a novel SR-BI methionine oxidation site with imatinib treatment. Conclusions: Our data supports the exploration of TKI-mediated SR-B1 regulation, HDL metabolism, and RCT mechanism to identify new therapeutic targets for dyslipidemia and ASCVD.