Abstract 1681: Haploinsufficiency of MEF2A Increases Risk of Atherosclerosis In Mice
MEF2A is a member of the myocyte enhancer factor-2 (MEF2) family of transcription factors. We showed that MEF2A was expressed in coronary arteries and mutations or rare variants of MEF2F were associated with risk of coronary artery disease (CAD) in humans. Both positive and negative replication studies were later reported. To further investigate the role of MEF2A in CAD and MI, we have characterized heterozygous MEF2A knockout mice and show here that haploinsufficiency of MEF2A in mice promotes atherosclerosis. Heterozygous MEF2A knockout mice were crossed to apoE-deficient mice, a widely used genetic model for atherosclerosis. The degree of atherogenesis was determined by the aortic root quantitative atherosclerosis assay. In vivo vascular permeability assay was performed using Evans blue dye upon stimulation with mustard oil in ears. Serum total cholesterol, HDL cholesterol, and triglyceride levels were measured with the Stanbio enzymatic kits. No significant differences were detected for total plasma cholesterol, HDL-C, VLDL-Cl and TG levels between MEF2A+ ApoE−/− mice and their MEF2A+/+ApoE−/− littermate controls (P = 0.14 – 0.44). The glucose levels before and after fasting were also similar between the two lines of mice (fasting, 106.25 ± 20.7 vs. 104.8 ± 21.9, P = 0.87; non-fasting, 175.3 ± 82 vs. 179.9 ± 119, P = 0.092). Total aortic lesion area was twofold greater in MEF2A+ApoE−/− mice than in MEF2A+/+ApoE−/− littermate controls fed on western diet (83408 μm2 vs. 46621 μm2 in males, n = 11 vs. 15, P = 0.0003; 137822 μm2 vs. 61568 μm2 in females, n = 12 vs. 9, P = 0.00003). Permeability of the vasculature in response to a proinflammatory stimulus was 3.2 fold higher in MEF2A+ApoE−/− mice than in MEF2A+/+ApoE−/− littermate controls (P = 0.000012). MEF2A haploinsufficiency promotes atherosclerotic lesion formation in mice, which may be due to increased vascular permeability. Lipid or glucose levels do not contribute to the formation of atherosclerotic lesions in these mice.