title: Implication of overexpression of dishevelled-associated activator of morphogenesis 1 (Daam-1) for the pathogenesis of human Idiopathic Pulmonary Arterial Hypertension (IPAH).
abstract: BACKGROUND
  Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins-namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)-in pulmonary arteries.
  
  
  METHODS
  We analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries.
  
  
  RESULTS
  Varying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls.
  
  
  CONCLUSIONS
  High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.
authors.affiliation: Department of Pediatrics, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Yanai
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan. megumi.wakayama@med.toho-u.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Wakayama
authors.affiliation: Department of Neurosurgery, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Shinozaki
authors.affiliation: Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Tsukuma
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Naobumi
authors.initials: N
authors.lastname: Tochigi
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nemoto
authors.affiliation: Advanced and Integrated Cardiovascular Research Course in the Young and Adolescence, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Saji
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000293:Adolescent; D000328:Adult; D065627:Familial Primary Pulmonary Hypertension / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D055815:Young Adult; D020741:rho GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C499094:DAAM1 protein, human; D008840:Microfilament Proteins; D020741:rho GTP-Binding Proteins
keywords: Daam-1; IPAH; Overexpression; Smooth muscle cells; Wnt/PCP pathway