Abstract Tu0058: Myeloid-specific deletion of <i>Diaph1</i> exhibits sex-dependent effects on lipid metabolism and necrotic core formation in <i> Ldlr ^-/- </i> mice

Background: Atherosclerosis is a major underlying cause of cardiovascular disease (CVD). During the early stages of atherosclerosis, monocytes and macrophages are attracted to sites of endothelial damage, where they contribute to lesional progression and necrotic core formation through lipid uptake, pro-inflammatory signaling, the production of damage associated molecular patterns (DAMPs) and the impaired clearance of lipids and cellular debris. Many of these DAMPs signal through the multi-ligand Receptor for Advanced Glycation End Products (RAGE) and its intracellular effector molecule, Diaphanous 1 (DIAPH1), which is important for RAGE signaling. We previously demonstrated that Ldlr -/- Diaph1 -/- mice fed a western diet exhibited less atherosclerosis and lower plasma and liver total cholesterol and triglycerides compared to Ldlr -/- control mice. While cell-specific roles of Diaph1 are not yet known, RAGE and DIAPH1 are expressed in monocytes/macrophages, and therefore may influence their role in the pathogenesis of atherosclerosis Hypothesis: Myeloid specific deletion of Diaph1 in Ldlr null mice will attenuate lipid content and atherosclerotic burden in male and female mice. Methods: We used the Cre-lox system to create Ldlr -/- male (n=5) and female (n8) mice with a myeloid-specific Diaph1 deletion ( Ldlr -/- Diaph1 (f/f) ΔMac ) and compared them to male (n=5) and female (n=6) control mice ( Ldlr -/- Diaph1 (f/f)). All mice were fed a western diet (0.15% cholesterol) for 16 weeks to induce atherosclerosis. Results: Myeloid deletion of Diaph1 resulted in no differences in atherosclerosis at the aortic sinus in male and female mice; however, female mice devoid of myeloid Diaph1 displayed a significant reduction in necrotic cores vs. controls (p=0.042). Further, although plasma concentrations of cholesterol and triglyceride and hepatic concentration of triglyceride did not differ between male mice devoid of myeloid Diaph1 vs. controls, female mice devoid of myeloid Diaph1 displayed significantly lower concentrations of plasma cholesterol (p=0.002) and triglyceride (p=0.007), and hepatic triglyceride (p=0.026) vs. myeloid Diaph1 -expressing controls. Conclusions: Our results indicate a sexual dimorphism in the functions of myeloid Diaph1 in atherosclerosis. The specific metabolic and immunological mechanisms underlying these changes in plasma and hepatic lipid concentrations are currently under investigation.