title: Disruption of phactr-1 pathway triggers pro-inflammatory and pro-atherogenic factors: New insights in atherosclerosis development.
abstract: Significant interest has recently emerged for phosphatase and actin regulatory protein (PHACTR1) gene in heart diseases prognosis. However, the functional role of phactr-1 protein remains elusive in heart related-diseases such as atherosclerosis, coronary artery calcification, ischaemic stroke, coronary artery stenosis and early-onset myocardial infarction. Phactr-1 is directly regulated by vascular endothelial growth factor A165 (VEGF-A165) through VEGF receptor 1 (VEGR-1) and Neuropilin-1 (NRP-1). Using an antagonist peptide approach to inhibit the interaction of VEGF-A165 to NRP-1 and VEGF-R1, we highlighted the importance of both cysteine residues located at the end of VEGF-A165 exon-7 and at the exon-8 to generate functional peptides, which decreased Phactr-1 expression. Here, we report original data showing Phactr-1 down-expression induces the expression of Matrix Metalloproteinase (MMP) regulators such as Tissue inhibitor of metalloproteinase (TIMP-1/-2) and Reversion-inducing-cysteine-rich protein with kazal motifs (RECK). Furthermore, focal adhesion kinases (FAK/PYK2/PAXILLIN) and metabolic stress (AMPK/CREB/eNOS) pathways were inhibited in endothelial cells. Moreover, the decrease of phactr-1 expression induced several factors implicated in atherosclerotic events such as oxidized low-density lipoprotein receptors (CD36, Clusterin, Cadherin-13), pro-inflammatory proteins including Thrombin, Thrombin receptor 1 (PAR-1), A Disintegrin And Metalloprotease domain-9/-17 (ADAM-9/-17), Trombospondin-2 and Galectin-3. Besides, Phactr-1 down-expression also induces emerging atherosclerosis biomarkers such as semicarbazide-sensitive amine oxidase (SSAO) and TGF-beta-inducible gene h3 (βIG-H3). In this report, we show for the first time the direct evidence of the phactr-1 biological function in the regulation of pro-atherosclerotic molecules. This intriguing result strengthened heart diseases PHACTR-1 single-nucleotide polymorphisms (SNP) correlation. Taken together, our result highlighted the pivotal role of phactr-1 protein in the pathogenesis of atherosclerosis.
authors.affiliation: Sup'Biotech, 66 Rue Guy Môquet, 94800 Villejuif, France; CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Division of Prions and Related Diseases (SEPIA), Fontenay-aux-Roses, France.
authors.forename: Rafika
authors.initials: R
authors.lastname: Jarray
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Division of Prions and Related Diseases (SEPIA), Fontenay-aux-Roses, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Pavoni
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Allain
authors.affiliation: ESG, 59 Rue Nationale, 75013 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lopez
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Bianco
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Wang-Qing
authors.initials: WQ
authors.lastname: Liu
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Division of Prions and Related Diseases (SEPIA), Fontenay-aux-Roses, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France; Institut de Chimie de Nice (ICN), UMR 7272 CNRS, Université de Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
authors.affiliation: INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, 24 Boulevard Montparnasse 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 Boulevard Montparnasse 75015 Paris, France; CNRS ERL 8254, 24 Boulevard Montparnasse 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France. Electronic address: francoise.raynaud@parisdescartes.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, 24 Boulevard Montparnasse 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 Boulevard Montparnasse 75015 Paris, France; CNRS ERL 8254, 24 Boulevard Montparnasse 75015 Paris, France. Electronic address: y.lepelletier@gmail.com.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D039921:Neuropilins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D039921:Neuropilins; C570134:PHACTR1 protein, human; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Atherosclerotic factors; MMP regulators; Neuropilin; Phactr-1; VEGF