title: The expression of groups IIE and V phospholipase A2 is associated with an increased expression of osteogenic molecules in human calcified aortic valves.
abstract: OBJECTIVE
  Eicosanoids play various pathogenic roles in aortic valve calcification. Eicosanoids are derived from the arachidonic acid generated by phospholipase A2 (PLA2). We therefore sought to determine whether PLA2s are expressed in human aortic valves and, if so, whether the expression of PLA2s is related to the expression of osteogenic molecules in these tissues.
  
  
  METHODS
  Histological and gene expression analyses of 38 non-rheumatic aortic valves obtained at the time of cardiac valve replacement surgery were conducted. Moreover, gene expression analyses were performed using valve interstitial cells (VICs) obtained from human aortic valves.
  
  
  RESULTS
  Among the PLA2s examined, the degree of immunoreactivity for PLA2s-IIE and -V was found to significantly correlate with the grade of calcification in the aortic valves. The degree of immunoreactivity and gene expression levels of PLA2s-IIE and -V significantly correlated with those of bone morphogenetic protein (BMP)-2, osteopontin and alkaline phosphatase (ALP). In addition, immunoreactivity for cyclooxygenase (COX)-1, COX-2 and 5-lipoxygenase, downstream enzymes of PLA2 in the arachidonic acid cascade, was co-localized with that for PLA2s-IIE and -V in cells expressing α-smooth muscle actin and macrophages expressing CD68. Furthermore, in the in vitro experiments using cultured VICs, the mRNA expression levels of BMP-2, osteopontin and ALP were suppressed by the inhibition of the expression of PLA2s-IIE or -V with specific siRNAs.
  
  
  CONCLUSIONS
  The expression of PLA2s-IIE and -V correlates with the development of calcification as well as the expression of pro-osteogenic molecules in human aortic valves, and inhibiting the expression of PLA2s-IIE and -V suppresses the induction of osteogenic molecules in cultured cells. Therefore, PLA2s-IIE and -V may play a role in the pathogenesis of valve calcification.
authors.affiliation: Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine.
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Soichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujioka
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Jun-ei
authors.initials: JE
authors.lastname: Obata
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kawabata
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.forename: Masahiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015992:Body Mass Index; D002114:Calcinosis / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D054505:Group V Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010012:Osteogenesis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001094:Arachidonate 5-Lipoxygenase; D008078:Cholesterol, LDL; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054501:Group II Phospholipases A2; D054505:Group V Phospholipases A2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C516299:PLA2G5 protein, human