Abstract 158: PPAP2B Expression Regulates the Development of Atherosclerosis

Coronary artery disease (CAD) is the leading cause of death in both men and women worldwide. The bioactive lipid lysophosphatidic acid (LPA) accumulates in human atheroma compared to levels in healthy control tissue. LPA can be degraded by the membrane protein lipid phosphate phosphatase 3 (LPP3), encoded by the gene PPAP2B. Noncoding polymorphisms in PPAP2B associate with CAD risk, and gene expression analysis indicates that individuals possessing the risk allele exhibit lower levels of PPAP2B mRNA in leukocytes and vascular cells. We hypothesize that decreased LPP3, as a result of low PPAP2B expression, accelerates experimental atherosclerosis. Murine models of tissue specific LPP3 knockdown were generated using the Cre-Lox system driven by either the MX-1 promoter (MX-1Δ) or the smooth muscle cell specific SM22 promoter (SM22Δ) in mice on the atherogenic LDLr -/- background. Following 12 weeks on Western diet, knockdown of LPP3 in both the MX-1Δ and the SM22Δ mice resulted in significantly more atherosclerosis by en face analysis compared to LPP3-fl/fl littermate controls. LPA content determined using LC/MS/MS tended to be higher in the proximal aortas of MX-1Δ and SM22Δ knockdown mice compared to controls. Significantly higher macrophage gene expression was observed in the MX-1Δ mice while IL-6 levels were significantly higher in the SM22Δ mice compared to controls. Finally, targeting LPP3 expression in the MX-1Δ, but not the SM22Δ, mice resulted in significantly higher circulating levels of LPA compared to controls. These results are consistent with accelerated atherosclerosis in LPP3 knockdown mice and suggest a protective role for LPP3 in CAD. Increased vascular LPA content, as a consequence of decreased LPP3 expression, may promote the infiltration of monocyte/macrophages into lesions as well as exacerbate inflammation to accelerate the development of CAD. Our findings provide mechanistic insight into the genome wide association studies that linked genetic variation in PPAP2B with risk of CAD and focus attention on the LPA/ LPP3 signaling nexus as a novel therapeutic strategy to prevent atherosclerosis.