title: Endothelin-1 induces VCAM-1 expression-mediated inflammation via receptor tyrosine kinases and Elk/p300 in human tracheal smooth muscle cells.
abstract: The elevated level of endothelin-1 (ET-1) has been detected in the bronchoalveolar lavage of patients with severe asthma, acute lung injury, acute respiratory distress syndrome, and sepsis. ET-1 may affect vessel tone together with lung physiology and pathology. Vascular cell adhesion molecule-1 (VCAM-1) is one kind of adhesion molecules participating in the process of polymorphonuclear leukocyte transmigration and regulating the occurrence and amplification of tissue inflammation. However, the molecular mechanisms underlying ET-1-mediated expression of VCAM-1 on human tracheal smooth muscle cells (HTSMCs) were largely unknown. Here we reported that ET-1 stimulated expression of VCAM-1 gene on HTSMCs, which was blocked by pretreatment with the inhibitors of ET receptors, Src, matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatidylinositol 3-kinase (PI3K), AKT, MEK1/2, and p300, suggesting the participation of these signaling components in ET-1-regulated HTSMC responses. Furthermore, transfection with small-interfering RNA (siRNA) of Src, AKT, p42 mitogen-activated protein kinase (MAPK), or p300 downregulated the respective proteins and significantly attenuated ET-1-induced VCAM-1 expression. ET-1 also stimulated phosphorylation of Src, EGFR, PDGFR, AKT, p42/p44 MAPK, and Elk-1 and acetylation of histone H4 on HTSMCs. Immunoprecipitation assay showed the association between Elk-1 and p300 in the nucleus. Adhesion assay revealed that the adhesion of THP-1 to HTSMCs challenged with ET-1 was increased, which was attenuated by the inhibitors of ET receptors, Src, MMPs, EGFR, PDGFR, PI3K, AKT, p42/p44 MAPK, and p300. Taken together, these data suggested that ET-1 promotes occurrence and amplification of pathology-related airway inflammation via enhancing VCAM-1 expression in an ET receptor/Src/MMP/EGFR, PDGFR/PI3K/AKT/p42/p44 MAPK/Elk-1/p300 pathway in HTSMCs.
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan;
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; and.
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Hou
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan;
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.affiliation: Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan chuenmao@mail.cgu.edu.tw.
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014132:Trachea / Q000473:pathology; D015533:Transcriptional Activation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: C494112:ELK1 protein, human; D019332:Endothelin-1; D043562:Receptors, G-Protein-Coupled; D019010:Vascular Cell Adhesion Molecule-1; D050807:ets-Domain Protein Elk-1; D050880:p300-CBP Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: human tracheal smooth muscle cells; vascular cell adhesion molecule-1