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Mueller, Paul A; Yang, Liping; Ubele, Margo; Mao, Guogen; Brandon, Jason; Vandra, Julia; Nichols, Timothy C; Escalante-Alcalde, Diana; Morris, Andrew J; Smyth, Susan S (2019)

CORONARY ARTERY DISEASE RISK-ASSOCIATED PLPP3 GENE AND ITS PRODUCT LIPID PHOSPHATE PHOSPHATASE 3 REGULATE EXPERIMENTAL ATHEROSCLEROSIS

Arterioscler. Thromb. Vasc. Biol. 39(11):2261-2272
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Genome-wide association studies identified novel loci in (phospholipid phosphatase 3) that associate with coronary artery disease risk independently of traditional risk factors. encodes LPP3 (lipid phosphate phosphatase 3), a cell-surface enzyme that can regulate the availability of bioactive lysophopsholipids including lysophosphatidic acid (LPA). The protective allele of increases LPP3 expression during cell exposure to oxidized lipids, however, the role of LPP3 in atherosclerosis remains unclear. Approach and Results: In this study, we sought to validate LPP3 as a determinate of the development of atherosclerosis. In experimental models of atherosclerosis, LPP3 is upregulated and co-localizes with endothelial, smooth muscle cell, and CD68-positive cell markers. Global post-natal reductions in expression in mice substantially increase atherosclerosis, plaque-associated LPA, and inflammation. Although LPP3 expression increases during ox-LDL (oxidized low-density lipoprotein)-induced phenotypic modulation of bone marrow-derived macrophages, myeloid does not appear to regulate lesion formation. Rather, smooth muscle cell LPP3 expression is a critical regulator of atherosclerosis and LPA content in lesions. Moreover, mice with inherited deficiency in LPA receptor signaling are protected from experimental atherosclerosis.