title: Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium.
abstract: Expression of cell adhesion molecules (CAM) responsible for leukocyte-endothelium interactions plays a crucial role in inflammation and atherogenesis. Up-regulation of vascular CAM-1 (VCAM-1), intracellular CAM-1 (ICAM-1), and E-selectin expression promotes monocyte recruitment to sites of injury and is considered to be a critical step in atherosclerotic plaque development. Factors that trigger this initial response are not well understood. As platelet activation not only promotes thrombosis but also early stages of atherogenesis, we considered the role of thrombospondin-1 (TSP-1), a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, as a regulator of CAM expression. TSP-1 induced expression of VCAM-1 and ICAM-1 on endothelium of various origins, which in turn, resulted in a significant increase of monocyte attachment. This effect could be mimicked by a peptide derived from the C-terminal domain of TSP-1 and known to interact with CD47 on the cell surface. The essential role of CD47 in the cellular responses to TSP-1 was demonstrated further using inhibitory antibodies and knockdown of CD47 with small interfering RNA. Furthermore, we demonstrated that secretion of endogenous TSP-1 and its interaction with CD47 on the cell surface mediates endothelial response to the major proinflammatory agent, tumor necrosis factor alpha (TNF-alpha). Taken together, this study identifies a novel mechanism regulating CAM expression and subsequent monocyte binding to endothelium, which might influence the development of anti-atherosclerosis therapeutic strategies.
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Narizhneva
authors.forename: Olga V
authors.initials: OV
authors.lastname: Razorenova
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
authors.forename: Juhua
authors.initials: J
authors.lastname: Chen
authors.forename: Unni M
authors.initials: UM
authors.lastname: Chandrasekharan
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D050197:Atherosclerosis / Q000209:etiology; D051928:CD47 Antigen / Q000502:physiology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1