Abstract 19366: NG2 Ablation Aggravates Obesity and Hyperlipidemia but Reduces Atherogenesis

Abstract

Background & Hypothesis: Ablation of chondroitin sulfate proteoglycan 4 (NG2) impairs brown fat development and function, leading to increased levels of serum lipids, increased lipid storage, and increased white fat mass. Since obesity and hyperlipidemia are two key risk factors for atherosclerosis, we wondered how NG2 ablation would affect atherogenesis. In addition to its expression by white and brown adipocytes, NG2 is also highly expressed by mesenchymal stromal cells (MSCs) in both human and mouse atherosclerotic plaques. NG2 could therefore could affect atherogenesis in the context of MSC function, as well as in the context of adipocyte function. Methods & Results: We compared atherosclerotic plaque formation between ApoE null/NG2 wild type and ApoE null/NG2 null mice fed with a Western diet. Body weight, serum cholesterol, and triglyceride levels are similar in the two lines of mice in the early (10 weeks) and middle (16 weeks) stages of atherogenesis. However, all three parameters are significantly increased in the double null mice after 26 weeks of high fat diet induction. Aortic plaque areas are also similar in the two mouse lines at 10 and 16 weeks, but are reduced by 30% in double null male mice after 26 weeks of induction. Lipid content, collagen content, and the abundance of macrophages, smooth muscle cells, and MSCs are all reduced in plaques by 20-30% in double null males at 26 weeks. Like other chondroitin sulfate proteoglycans, purified NG2 exhibits strong LDL binding in ELISA tests. At the cellular level, cultured NG2 null MSCs bind less LDL than wild type MSCs. In vivo, LDL retention in NG2/ApoE double knock-out plaques is about 30% less than that seen in ApoE null/NG2 wild type plaques. Summary & Significance: In spite of the obese and hyperlipidemic phenotype of ApoE null/NG2 null mice during later stages of atherogenesis, the absence of NG2 nevertheless results in less retention of LDL in the mouse aorta, thus restricting plaque expansion. Inhibition of NG2 may be a promising therapeutic strategy for atherosclerosis and related diseases.