title: Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces.
abstract: BACKGROUND
  PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genome-wide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis.
  
  
  OBJECTIVE
  To establish the critical role of PPAP2B in endothelial responses to hemodynamics.
  
  
  RESULTS
  Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells.
  
  
  CONCLUSIONS
  Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow.
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Congqing
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Ru-Ting
authors.initials: RT
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Cheng-Hsiang
authors.initials: CH
authors.lastname: Kuo
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Los Angeles.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Los Angeles.
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Yen-Chen
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Anna
authors.initials: A
authors.lastname: Birukova
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Nickolai O
authors.initials: NO
authors.lastname: Dulin
authors.affiliation: Department of Medicine, University of California, Los Angeles.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Department of Medicine, University of California, Los Angeles.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Paris-Cardiovascular Research Center, University Paris Descartes.
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.affiliation: Paris-Cardiovascular Research Center, University Paris Descartes.
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.affiliation: Department of Biomedical Engineering, Rensselaer Polytechnic Institute.
authors.forename: Guohao
authors.initials: G
authors.lastname: Dai
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Los Angeles.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.affiliation: Department of Medicine, University of Chicago, Los Angeles.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000503:physiopathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001665:Binding Sites; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006439:Hemodynamics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010641:Phenotype; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D018994:Myosin Light Chains; D049368:Receptors, Lysophosphatidic Acid; C521833:PLPP3 protein, human; D010711:Phosphatidate Phosphatase; C479566:Plpp3 protein, mouse
keywords: atherosclerosis; endothelial cells; genome wide association study; hemodynamics; microRNAs; permeability