Abstract 467: Lipid Phosphate Phosphatase 3 in Smooth Muscle Cells Suppresses the Development of Atherosclerosis

Abstract

Lipid phosphate phosphatase3 (LPP3) encoded by the PPAP2B gene, is an integral membrane enzyme that degrades bioactive lysophospholipids including lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P) and related bioactive lipids. These bioactive lipids regulate a wide variety of cellular functions such as proliferation, apoptosis and differentiation. We suggest that LPP3 hydrolysis of LPA is a critical step in regulating pathophysiological important responses in vascular cells. To test this hypothesis, we generated mice lacking LPP3 by breeding Ppap2B fl / fl mice (fl/fl) animals expressing Cre recombinase under control of the SM22 promoter on the LDLr-/- background. At weaning, littermate SM22-Δ and fl/fl mice were fed Western Diet (WD) for 12 weeks. LPP3 expression in aortic SMCs was reduced (0.139 ± 0.0246 vs 1.0 ± 0; P < 0.001) and LPA content was significantly higher (9.32 ± 4.66 vs 5.66 ± 2.65; P < 0.05) in the aortic arch in SM22-Δ mice compared to control fl/fl mice. SM22-Δ mice demonstrated increased atherosclerotic lesions (18.98 ± 7.11% vs 6.06 ± 4.01%; P < 0.001), measured by en face analysis, of the aorta and significantly higher IL-6 expression (18.83 ± 2.87 vs 3.59 ± 8.92; P < 0.05) in the aortic arch. Sections of aorta at the level of the aortic root indicated that the loss of LPP3 upregulate CD68 and α-SMA staining. These results reveal that LPP3 normally functions to suppress atherosclerosis. LPP3 deficiency increases vascular LPA content, may promote the infiltration of inflammatory cells as macrophages into lesions and smooth muscle cell proliferation to accelerate the development of atherosclerosis.