Abstract 535: Lipid Phosphate Phosphatase 3: A Novel Mediator of Heart Failure Development and Progression
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is found in abundance in atherosclerotic plaques and whose production is accelerated by activated platelets. Two fold rise in serum LPA concentration in acute myocardial infarct patients (6.4±1.3 micro mol/L vs 2.5 ± 1.1 micro mol/L, P = 0.0001) and its effect to cause cardiomyocyte hypertrophy suggests, a critical role for LPA regulation in the myocardium. The actions of local and circulating LPA may be terminated by enzymatic dephosphorylation of the lipid by a family of hexahelical membrane spanning proteins, termed lipid phosphate phosphatases (LPP). Of the three LPP enzymes with preference for LPA, LPP3 appears the most likely to play a biologic role in regulating LPA levels, and deficiency of LPP3 results in embyronic lethality in mice due to vascular and neural tube defects. We have generated mice that specifically lack LPP3 in cardiomyocytes. These mice are viable and fertile but showed increased mortality ~8 months (Fig1). 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 cardiomyocyte hypertrophy induced by LPA.
Author Disclosures: M. Panchatcharam: None. B. Maxey: None. A. Day: None. D. Escalante-Alcalde: None. S. Miriyala: None.
- © 2015 by American Heart Association, Inc.