title: Thrombomodulin, a novel molecule regulating inorganic phosphate-induced vascular smooth muscle cell calcification.
abstract: Hyperphosphatemia has emerged as a cardiovascular risk factor that stimulates calcification in vessels. We explored molecules that were induced by inorganic phosphate (Pi) at an early stage in vascular smooth muscle cells (VSMC). In the present study, we examined the role of thrombomodulin (TM) in Pi-induced VSMC calcification based on the results of DNA microarray analysis. Both mRNA and protein expression of TM were markedly augmented in Pi-induced calcification. Conversely, knockdown of TM by siRNA significantly inhibited calcification, in addition to Pi-induced apoptosis which plays critical roles in VSMC calcification. We further found that TM suppressed both of mRNA and protein expression of growth arrest-specific gene 6 (Gas6), a key molecule regulating apoptosis. Recombinant extracellular epidermal growth factor (EGF)-repeat domain of TM exaggerated calcification and this effect was abrogated by a neutralizing antibody for EGF receptor, suggesting that the cleaved and secreted form of TM may activate EGF receptor. We also found that downregulation of Gas6 by TM/EGF receptor axis was mediated by ERK in VSMC calcification. In the aorta of adenine-fed rat, a typical medial calcification model with hyperphosphatemia, we found that TM expression was increased. Furthermore, in human calcified aorta, increased TM expression was also observed. These results indicate that TM is a novel molecule that promotes apoptosis and vascular calcification by regulation of Gas6, presumably via EGF receptor/ERK axis.
authors.affiliation: Department of Geriatric Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Son
authors.forename: Masahiro
authors.initials: M
authors.lastname: Akishita
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iijima
authors.forename: Sumito
authors.initials: S
authors.lastname: Ogawa
authors.forename: Tomio
authors.initials: T
authors.lastname: Arai
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ishii
authors.forename: Koji
authors.initials: K
authors.lastname: Maemura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Masato
authors.initials: M
authors.lastname: Eto
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010710:Phosphates / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D061205:Vascular Calcification / Q000378:metabolism* / Q000473:pathology; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D036341:Intercellular Signaling Peptides and Proteins; D010710:Phosphates; D018180:Thrombomodulin; D000099255:Growth Arrest-Specific Protein 6