1. Role of lipid phosphate phosphatase 3 in human aortic endothelial cell function
- Author
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Yuna Blum, Henri Weidmann, Mete Civelek, Aldons J. Lusis, Zahia Touat-Hamici, Veronica Codoni, Ewa Ninio, Pauline Gaignard, Carole Proust, Francesca Iannacci, Sonia Karabina, Patrice Therond, François Cambien, Hervé Durand, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Université Paris-Sud - Paris 11 (UP11), Service de Biochimie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Sante et de la Recherche Medicale and the Transatlantic Networks of Excellence, Fondation Leducq (12CVD02) (France)National Institutes of Health (USA) grants (HL28481 and K99HL121172), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), HAL-UPMC, Gestionnaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of California-University of California, Physiopathologie des maladies génétiques d'expression pédiatrique, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Physiology ,Angiogenesis ,medicine.medical_treatment ,Apoptosis ,Substrate Specificity ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Sphingosine ,Catalytic Domain ,Lysophosphatidic acid ,Endothelial dysfunction ,Aorta ,Cells, Cultured ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Cell biology ,Endothelial stem cell ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Cytokine ,030220 oncology & carcinogenesis ,Cytokines ,RNA Interference ,lipids (amino acids, peptides, and proteins) ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,Primary Cell Culture ,Phosphatidate Phosphatase ,Neovascularization, Physiologic ,Biology ,Transfection ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Protein Domains ,Physiology (medical) ,Cell Adhesion ,medicine ,Humans ,Cell adhesion ,Endothelial Cells ,Original Articles ,Atherosclerosis ,medicine.disease ,030104 developmental biology ,chemistry ,Mutation ,Lysophospholipids - Abstract
Aims Lipid phosphate phosphatase 3; type 2 phosphatidic acid phosphatase β (LPP3; PPAP2B ) is a transmembrane protein dephosphorylating and thereby terminating signalling of lipid substrates including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). Human LPP3 possesses a cell adhesion motif that allows interaction with integrins. A polymorphism (rs17114036) in PPAP2B is associated with coronary artery disease, which prompted us to investigate the possible role of LPP3 in human endothelial dysfunction, a condition promoting atherosclerosis. Methods and results To study the role of LPP3 in endothelial cells we used human primary aortic endothelial cells (HAECs) in which LPP3 was silenced or overexpressed using either wild type or mutated cDNA constructs. LPP3 silencing in HAECs enhanced secretion of inflammatory cytokines, leucocyte adhesion, cell survival, and migration and impaired angiogenesis, whereas wild-type LPP3 overexpression reversed these effects and induced apoptosis. We also demonstrated that LPP3 expression was negatively correlated with vascular endothelial growth factor expression. Mutations in either the catalytic or the arginine-glycine-aspartate (RGD) domains impaired endothelial cell function and pharmacological inhibition of S1P or LPA restored it. LPA was not secreted in HAECs under silencing or overexpressing LPP3. However, the intra- and extra-cellular levels of S1P tended to be correlated with LPP3 expression, indicating that S1P is probably degraded by LPP3. Conclusions We demonstrated that LPP3 is a negative regulator of inflammatory cytokines, leucocyte adhesion, cell survival, and migration in HAECs, suggesting a protective role of LPP3 against endothelial dysfunction in humans. Both the catalytic and the RGD functional domains were involved and S1P, but not LPA, might be the endogenous substrate of LPP3.
- Published
- 2016
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