Abstract 215: Enhanced Atherosclerosis, Inflammation And Oxidized Phospholipid Reactivity In Female Transgenic Mice Expressing Human Lp(a)

Abstract

Despite increased clinical interest in the unique lipoprotein Lp(a), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. To address this knowledge gap we generated transgenic mice expressing both human apolipoprotein(a) (apo(a)) and human apoB100 (Tg(LPA +/0 ;APOB +/0 )), with pathogenic levels of plasma Lp(a) (mean 134 mg/dL; range 87–250 mg/dL). Female mice (n=12/group) were fed a high-fat, high-cholesterol diet and injected weekly with an antisense oligonucleotide targeting the Ldlr for 12 weeks to induce atherosclerosis. FPLC demonstrated that both Tg(LPA +/0 ;APOB +/0 ) and Tg(APOB +/0 ) mice exhibited proatherogenic lipoprotein profiles (increased cholesterol-rich VLDL and LDL-sized particles) and developed complex lesions in the aortic sinus. However, Oil Red O-staining reveled significantly increased plaque area (+23%) in Tg(LPA +/0 ;APOB +/0 ) mice, compared to Tg(APOB +/0 ) mice. Examination of lesion pathology indicated more severe disease in Tg(LPA +/0 ;APOB +/0 ) mice, with significantly increased necrotic core size (41.8±2.8% vs. 33.4±2.7%, (p<0.05)) and calcium deposition (2.96±0.3% vs. 1.79±0.4%, (p<0.05)). Furthermore, Picrosirius Red staining showed a significant, 1.2-fold increase in collagen abundance in lesions of Tg(LPA +/0 ;APOB +/0 ) vs. Tg(APOB +/0 ) mice. Immunohistochemistry on the lesions demonstrated that in Tg(LPA +/0 ;APOB +/0 ) mice, Lp(a) colocalized with apoB100, CD68-positive macrophages and E06/oxidized phospholipid (OxPL). Compared to Tg(APOB +/0 ) mice, quantitation of the E06/OxPL-positively stained area revealed a significant increase (+39%) in Tg(LPA +/0 ;APOB +/0 ) mice. Female Tg(LPA +/0 ;APOB +/0 ) mice also had a 2-fold increase in E06/OxPL apo(a) in plasma, as well as enhanced circulating levels of the proinflammatory cytokines TNFα (1.2-fold increase) and MCP-1 (2.8-fold increase) compared to Tg(APOB +/0 ) mice. Taken together these data suggest an exacerbated pro-inflammatory phenotype in female Tg(LPA +/0 ;APOB +/0 ) mice, potentially contributing to the development of more advanced lesions. Further study of this novel mouse model will aid in the understanding of the fundamental role of elevated Lp(a) in atherogenesis.