Overexpression of constitutively active NPR-B inhibits cardiac hypertrophy

• Project/Area Number: 25461620
• 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: OKADA YOKO 大阪大学, 医学(系)研究科(研究院), 招へい教員 (30457022)
• Co-Investigator(Kenkyū-buntansha): KOGAKI Shigetoyo 大阪大学, 医学(系)研究科(研究院), 講師 (00311754) ; 高橋 邦彦 大阪大学, 医学(系)研究科(研究院), 助教 (10610230)
• Co-Investigator(Renkei-kenkyūsha): TAKAHASHI Kunihiko 大阪大学, 医学(系)研究科(研究院), 招へい教員 (10610230)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: NPR-B / CNP / cyclic GMP / 心不全

Outline of Final Research Achievements

We have identified a novel missense mutation in the NPR-B gene (2647G>A; Val 883 Met) in a family case showing overgrowth and bone anomalies. Overexpression of this constitutively active NPR-B (MT) induced significant increase in intracellular cGMP levels without CNP binding. We investigated a hypothesis that overexpression of MT inhibits cardiac hypertrophy.
To overexpress MT especially in heart, we used recombinant adeno-associated viral serotype-9 (rAAV-9) vectors. 10-week-old mice were subcutaneously implanted a miniosmotic pump that released isoproterenol. Tail vain injection of rAAV-9 vector was administered after the pump implantation. We investigate the heart body weight ratios (HW/BW), echocardiography, and histological analysis of heart (cell size .etc).As a result, overexpression of MT in heart inhibited ISO-induced cardiac hypertrophy compared to GFP control.
MT-NPRB may be an additional therapeutic target in the treatment of cardiac hypertrophy.

Research Products

• [Presentation] B型ナトリウム利尿ペプチド受容体（NPR-B）の機能獲得型変異体による心肥大抑制効果の検討 (2015)
  • Author(s): 馬殿 洋樹
  • Organizer: 第24回 小児心筋疾患学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-24
• [Presentation] B型ナトリウム利尿ペプチド受容体(NPR-B)の機能獲得型変異体による心不全治療戦略 (2014)
  • Author(s): 馬殿洋樹, 那波伸敏, 島越史子, 三原聖子, 石井 良, 市森裕章, 高橋邦彦, 岡田陽子, 小垣滋豊, 大薗恵一
  • Organizer: 第50回日本小児循環器学会学術集会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-07-03 – 2014-07-05
• [Presentation] 機能獲得変異型N-PRBによる心不全治療戦略 (2013)
  • Author(s): 馬殿洋樹, 髭野亮太, 那波伸敏, 石井 良, 市森裕章, 内川俊毅, 高橋邦彦, 岡田陽子, 小垣滋豊, 大薗恵一
  • Organizer: 第49回日本小児循環器学会総会
  • Place of Presentation: 国立オリンピック記念青少年総合センター
• [Presentation] Constitutively Active NPR-B (Type-B Human Natriuretic Peptide Receptor) Inhibits Cardiomyocyte Hypertrophy and Cardiac Fibroblast Fibrosis (2013)
  • Author(s): Baden H, Nawa N, Ishida H, Takahashi K, Kogaki S, Yabushita-Okada Y, Ichimori H, Ishii R, Mihara S, Higeno R, Miura K, Ozono K.
  • Organizer: AHA2013
  • Place of Presentation: Dallas, Texas, USA