Abstract 342: Lack of Lipid Phosphate Phosphatase 3 Promotes Cardiac Dysfunction and Early Mortality in Mice
Lysophosphatidic acid (LPA) is a naturally occurring glycerophospholipid and has been reported to increase heart rate and left ventricular pressure in the heart in vivo. The primary route of circulating LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin (ATX). Lipid phosphate phosphatase-3 (LPP3) is a plasma membrane enzyme that regulates the availability of LPA by dephosphorylation. We made the novel discovery that tissue-specific deficiency of Ppap2b (gene that encodes LPP3) leads to embryonic lethality (endothelial LPP3), exaggerates vascular inflammation, increases heart rate, enhances endothelial permeability, and promotes the development of the neointima after vascular injury. Based on our earlier reports, we have generated mice that specifically lack LPP3 in cardiomyocytes. These mice showed early mortality ~8 months due to cardiac dysfunction. Whereas lack of LPP1 or LPP2 (global knockouts) didn’t had any obvious phenotypic effect. Lack of LPP3 accounts for less than 10 percent activity in cardiomyocytes purified from the Myh6-Ppap2bΔ, which augments our previous finding that the other two LPP isoforms have a lesser role in the cardiovascular system. Blood pressure was similar in Ppap2bfl/fl (96 ± 9 mmHg; n = 19) and Myh6-Ppap2bΔ mice (92 ± 7 mmHg; n = 19), although heart rates were significantly higher in Myh6-Ppap2bΔ 3-month old mice (642 ± 21 bpm, compared to Ppap2bfl/fl with 600± 17 bpm; P<0.001). Knockdown of LPP3 enhanced cardiomyocyte hypertrophy induced by LPA based on analysis of sarcomere organization, cell surface area, levels of fetal genes ANP and BNP, and ANF release from nuclei, which are hallmarks of cardiomyocyte hypertrophy, indicating that LPP3 negatively regulates cardiac dysfunction caused by LPA. We observed an increase in ATX levels accompanied by a decrease in LPP3 expression following infarction in the myocardium of Ppap2bfl/fl mice. Infarction induced expression of IL-6 and KC, were 3 ± 0.5-fold and 2 ± 0.6-fold higher, respectively, in Myh6-Ppap2bΔ mice. Analysis of plasma by cytokine antibody array confirmed the elevation in IL-6 and KC, whereas G-CSF and sICAM-1 appeared lower than in Ppap2bfl/fl.
Author Disclosures: M. Panchatcharam: None. M. Chandra: None. B. Maxey: None. A. Day: None. D. Escalante-Alcalde: None. S. Miriyala: None.
- © 2015 by American Heart Association, Inc.