Abstract 18875: 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. We hypothesize that decreased LPP3, as a result of low PPAP2B expression, accelerates experimental atherosclerosis. An inducible knockout of LPP3 was generated using the Cre-Lox system driven by the MX-1 promoter in mice on the atherogenic LDL receptor deficient background. Broad knockdown of LPP3 was achieved with IP injection of a synthetic double stranded RNA (pI:pC) at age 3-5 days. After 12 weeks on Western diet, LPP3 knockdown mice developed significantly more atherosclerosis by en face analysis compared to littermate controls. Additionally, LPA content determined with LC/MS/MS tended to be higher in the proximal aortas of LPP3 knockdown mice. Real-time PCR analysis indicated significantly higher macrophage gene expression (CD68) in the LPP3 knockdowns 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 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.
Author Disclosures: P. Mueller: None. A. Morris: None. S. Smyth: None.
- © 2014 by American Heart Association, Inc.