Type B Human Natriuretic Peptide Receptor with a novel gain-of-function mutation provides therapeutic potential in the treatment of pulmonary arterial hypertension.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591567
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Osaka University
• Principal Investigator: KOGAKI Shigetoyo 大阪大学, 医学(系)研究科(研究院), 講師 (00311754)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Kunihiko 大阪大学, 医学(系)研究科(研究院), 特任助教(常勤) (10610230) ; ICHIMORI Hiroaki 大阪大学, 医学部附属病院, 医員 (60467553) ; NAWA Nobutoshi 大阪大学, 医学部附属病院, 医員 (30617543) ; ISHIDA Hidekazu 大阪大学, 医学部附属病院, 医員 (50467552)
• Project Period (FY): 2011 – 2013
• Keywords: 肺高血圧症 / CNP / ナトリウム利尿ペプチド受容体 / cGMP

Research Abstract

Recently, we have reported a novel missense mutation in the NPR-B gene (2647G>A; Val 883 Met) in a family case showing overgrowth and bone anomalies.We have found that overexpression of the mutated protein in human pulmonary artery smooth muscle cells (PASMCs) induced significant increase in cGMP levels compared to WT-NPR-B or GFP control in a ligand-independent manner. Overexpression of Mut-NPR-B suppressed proliferation in PASMCs. In vivo, rats treated with the combination of SU5416 and hypoxia developed pulmonary hypertension, right ventricular hypertrophy and pulmonary vascular obstructive lesions. Intratracheal administration of adenoviral vectors carrying Mut-NPR-B resulted in tendency toward an improvement in vascular remodeling as measured by medial wall thickness of pulmonary vessels compared to WT-NPR-B or GFP control
(GFP, 52+-13%; WT-NPR-B, 50+-4%; Mut-NPR-B, 44+-2 %, n=4).

Research Products

• [Presentation] Therapeutic Application of Type B Natriuretic Peptide Receptor With a Novel Gain-of-function Mutation in the Treatment of Pulmonaly Arterial Hypertension (2013)
  • Author(s): Nawa N, Ishida H, Baden H, Takahashi K, Kogaki S, Yabushita-Okada Y, Ichimori H, Ishii R, Mihara S, Higeno R, Miura K, Ozono K.
  • Organizer: American Heart Association, Scientiic Sessions 2013
  • Place of Presentation: 米国Dallas
  • Year and Date: 20131116-20
• [Presentation] C-type natriuretic peptide(CNP)受容体(NPR-B)の機能獲得型変異体を用いた、肺高血圧症に対する新たな治療アプローチ(第3報) (2013)
  • Author(s): 那波伸敏,石田秀和,馬殿洋樹,高橋邦彦,小垣滋豊,市森裕章,石井良,髭野亮太,藪下陽子,三浦弘司,大薗恵一
  • Organizer: 第49回日本小児循環器学会総会
  • Place of Presentation: 東京
  • Year and Date: 20130711-13
• [Presentation] C-type natriuretic peptide (CNP)受容体(NPR-B)の機能獲得型変異体を用いた、肺動脈性高血圧症(PAH)に対する新たな治療アプローチ (2013)
  • Author(s): 那波伸敏,石田秀和,馬殿洋樹,高橋邦彦,小垣滋豊,市森裕章,内川俊毅,石井良,髭野亮太,岡田陽子,三浦弘司,大薗恵一
  • Organizer: 第19回日本小児肺循環研究会
  • Place of Presentation: 東京
  • Year and Date: 2013-02-02
• [Presentation] C-type natriuretic peptide(CNP)受容体(NPR-B)の機能獲得型変異体を用いた、肺動脈性肺高血圧症に対する新たな治療アプローチ(第2報) (2012)
  • Author(s): 那波伸敏,石田秀和,高橋邦彦,小垣滋豊,市森裕章,内川俊毅,藪下陽子,三原聖子,馬殿洋樹,三浦弘司,大薗恵一
  • Organizer: 第48回日本小児循環器学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 20120705-07
• [Presentation] C-type natriuretic peptide (CNP)受容体(NPR-B)の機能獲得型変異体を用いた,肺動脈高血圧症(PAH)に対する新たな治療アプローチ (2012)
  • Author(s): 那波伸敏,石田秀和,高橋邦彦,小垣滋豊,市森裕章,内川俊毅,成田淳,岡田陽子,三浦弘司,大薗恵一
  • Organizer: 第18回日本小児肺循環研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-02-04
• [Presentation] Type B Human Natriuretic Peptide Receptor with a novel gain-of-function mutation provides therapeutic potential in the treatment of pulmonary arterial hypertension (2011)
  • Author(s): Nawa N, Ishida H, Kogaki S, Uchikawa T, Okada Y, Narita J, Maekawa S, Ichimori H, Miura K, Ozono K.
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: 米国オーランド
  • Year and Date: 2011-11-14