Induction of pulmonary hypertension by inflammatory stimuli in mice with genetically reduced BMPR2

• Project/Area Number: 23591565
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Mie University
• Principal Investigator: SAWADA Hirofumi 三重大学, 医学(系)研究科(研究院), 助教 (30362354)
• Co-Investigator(Kenkyū-buntansha): MARUYAMA Kazuo 三重大学, 医学系研究科, 教授 (20181828) ; 三谷 義英 三重大学, 医学部附属病院, 准教授 (60273380)
• Co-Investigator(Renkei-kenkyūsha): MITANI Yoshihide 三重大学, 医学部附属病院, 准教授 (60273380)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 肺高血圧 / 炎症

Research Abstract

Role of BMPR2 mutation in the pathogenesis of pulmonary arterial hypertension (PAH) has not been established. The inflammatory mechanisms are shown to be involved in clinical and experimental pathology of PAH. This study was planned to clarify the association of inflammatory mechanisms and BMPR2 gene mutation in the context of pulmonary hypertension by using the genetically modified animal models. We administered TNF alpha to BMPR2 hetero knockout (+/-) mice or control mice and assessed pulmonary hypertension and vascular lesions. Twoweek administration of TNF alpha did not induce pulmonary hypertension nor pulmonary vascular disease in the BMPR2 (+/-) mice. GMCSF administration aggravated hypoxia induced pulmonary hypertension in wild type mice, and anti GMCSF antibody administration improved the hypoxia induced pulmonary hypertension. Thus, an association of inflammatory mechanisms induced by reduced BMPR2 with pulmonary hypertension was demonstrated using animal models.

Research Products

• [Journal Article] Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension (2014)
  • Author(s): Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs G, Januszyk M, Cao A, Lai YJ, Perez Vde J, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, Rabinovitch M.
  • Journal Title: J Exp Med Volume: 211(2) Pages: 263-280
• [Journal Article] Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension (2014)
  • Author(s): Yamada Y, Maruyama J, Zhang E, Okada A, Yokochi A, Sawada H, Mitani Y, Hayashi T, Suzuki K, Maruyama K.
  • Journal Title: J Anesth Volume: 28(1) Pages: 26-33
• [Journal Article] Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. (2014)
  • Author(s): Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs G, Januszyk M, Cao A, Lai YJ, Perez Vde J, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, Rabinovitch M.
  • Journal Title: Journal of Experimental Medicine Volume: 211 Issue: 2 Pages: 263-280
  • DOI: 10.1084/jem.20111741
  • Peer Reviewed
• [Journal Article] FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension (2013)
  • Author(s): Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Rabinovitch M.
  • Journal Title: J Clin Invest Volume: 123(8) Pages: 3600-3613
• [Journal Article] Public access defibrillation improved the outcome after out-of-hospital cardiac arrest in school-age children : a nationwide, population-based, Utstein registry study in Japan (2013)
  • Author(s): Mitani Y, Ohta K, Yodoya N, Otsuki S, Ohashi H, Sawada H, Nagashima M, Sumitomo N, Komada Y.
  • Journal Title: Europace Volume: 15(9) Pages: 1259-1266
• [Journal Article] Chronic effects of pulmonary artery stenosis on hemodynamic and structural development of the lungs (2013)
  • Author(s): Razavi H, Stewart SE, Xu C, Sawada H, Zarafshar SY, Taylor CA, Rabinovitch M, Feinstein JA.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 304(1)
• [Journal Article] Chronic effects of pulmonary artery stenosis on hemodynamic and structural development of the lungs. (2013)
  • Author(s): Razavi H, Stewart SE, Xu C, Sawada H, Zarafshar SY, Taylor CA, Rabinovitch M, Feinstein JA.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 304 Issue: 1 Pages: L17-L28
  • DOI: 10.1152/ajplung.00412.2011
  • Peer Reviewed
• [Journal Article] Loss of adenomatous poliposis coli-α3 integrin interaction promotes endothelial apoptosis in mice and humans (2012)
  • Author(s): de Jesus Perez VA, Yuan K, Orcholski ME, Sawada H, Zhao M, Nickel N, Rajagopalan V, Spiekerkoetter E, Wang L, Dutta R, Bernstein D, Rabinovitch M.
  • Journal Title: Circ Res Volume: 111(12) Pages: 1551-1564
• [Journal Article] Loss of adenomatous poliposis coli-α3 integrin interaction promotes endothelial apoptosis in mice and humans. (2012)
  • Author(s): de Jesus Perez VA, Yuan K, Orcholski ME, Sawada H, Zhao M, Li CG, Tojais NF, Nickel N, Rajagopalan V, Spiekerkoetter E, Wang L, Dutta R, Bernstein D, Rabinovitch M.
  • Journal Title: Circ Res. Volume: 111 Issue: 12 Pages: 1551-64
  • DOI: 10.1161/circresaha.112.267849
  • Peer Reviewed
• [Journal Article] Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival (2011)
  • Author(s): Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Rabinovitch M.
  • Journal Title: J Clin Invest Volume: 121(9) Pages: 3735-3746
• [Journal Article] Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions (2011)
  • Author(s): Kim YM, Haghighat L, Spiekerkoetter E, Sawada H, Alvira CM, Wang L, Acharya S, Rodriguez-Colon G, Orton A, Zhao M, Rabinovitch M.
  • Journal Title: Am J Pathol Volume: 179(3) Pages: 1560-1572
• [Journal Article] Quantitative characterization of postnatal growth trends in proximal pulmonary arteries in rats by phase-contrast magnetic resonance imaging (2011)
  • Author(s): Razavi H, Zarafshar SY, Sawada H, Taylor CA, Feinstein JA.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 301(3)
• [Journal Article] BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways (2011)
  • Author(s): Perez VA, Ali Z, Alastalo TP, Ikeno F, Sawada H, Lai YJ, Kleisli T, Spiekerkoetter E, Qu X, Rubinos LH, Ashley E, Amieva M, Dedhar S, Rabinovitch M.
  • Journal Title: J Cell Biol Volume: 192(1) Pages: 171-188
• [Journal Article] Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension (2011)
  • Author(s): Lee SJ, Smith A, Guo L, Alastalo TP, Li M, Sawada H, Liu X, Chen ZH, Ifedigbo E, Jin Y, Feghali-Bostwick C , Kim HP, Rabinovitch M, Choi AM.
  • Journal Title: Am J Respir Crit Care Med Volume: 183(5) Pages: 649-658
• [Journal Article] Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. (2011)
  • Author(s): Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Freeman BA, Chang HY, Rabinovitch M.
  • Journal Title: J Clin Invest Volume: 121 Issue: 9 Pages: 3735-46
  • DOI: 10.1172/jci43382
  • Peer Reviewed
• [Journal Article] Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. (2011)
  • Author(s): Kim YM, Haghighat L, Spiekerkoetter E, Sawada H, Alvira CM, Wang L, Acharya S, Rodriguez-Colon G, Orton A, Zhao M, Rabinovitch M
  • Journal Title: Am J Pathol Volume: 179 Pages: 1560-72
  • Peer Reviewed
• [Journal Article] Quantitative characterization of postnatal growth trends in proximal pulmonary arteries in rats by phase-contrast magnetic resonance imaging. (2011)
  • Author(s): Razavi H, Zarafshar SY, Sawada H, Taylor CA, Feinstein JA
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 301
  • Peer Reviewed
• [Journal Article] BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways (2011)
  • Author(s): Perez VA, Ali Z, Alastalo TP, Ikeno F, Sawada H, Lai YJ, Kleisli T, Spiekerkoetter E, Qu X, Rubinos LH, Ashley E, Amieva M, Dedhar S, Rabinovitch M
  • Journal Title: J Cell Biol. Volume: 192 Pages: 171-88
  • Peer Reviewed
• [Presentation] Early Detection of Pediatric Idiopathic Pulmonary Arterial Hypertension by School Electrocardiography Screening : a Nationwide Survey in Japan (2013)
  • Author(s): Sawada H, Mitani Y, Nakayama T, Fukushima H, Kogaki S, Igarashi T, Ichida F, Ono Y, Nakanishi T, Doi S, Ishikawa S, Matsushima M, Yamada O and Saji T.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas,USA
  • Year and Date: 2013-11-20
• [Presentation] Phenotypic Modulation of Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats (2013)
  • Author(s): Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Imanaka K, Shimpo H, Zhang E, Maruyama K, Komada Y, Mitani Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, USA
  • Year and Date: 2013-11-17
• [Presentation] Marlene Rabinovitch肺高血圧において、BMPR2減少から炎症細胞浸潤に至る機序 (2013)
  • Author(s): 澤田博文、三谷義英、大槻祥一郎、淀谷典子、大橋啓之、丸山一男、駒田美弘
  • Organizer: 第2回日本肺循環学会シンポジウム『肺高血圧発症の分子生物学的アプローチ』
  • Place of Presentation: 東京
  • Year and Date: 2013-06-22
• [Presentation] Marlene Rabinovitch. Reduced BMPR-II Induces GM-CSF Translation by Impaired Stress Granule Response, Exacerbating Pulmonary Hypertension (2012)
  • Author(s): 澤田博文、三谷義英、大槻祥一郎、淀谷典子、大橋啓之、丸山一男、駒田美弘
  • Organizer: 第76回日本循環器学会学術集会シンポジウム『肺高血圧治療の最前線』
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-16
• [Presentation] Reduced BMPR-II Induces GM-CSF Translation by Impaired Stress Granule Response, Exacerbating Pulmonary Hypertension (2012)
  • Author(s): 澤田 博文
  • Organizer: 日本循環器学会学術集会 シンポジウム
  • Place of Presentation: 福岡市
• [Presentation] Reduced BMPR-II Increases GM-CSF mRNA Translation by Inhibiting eIF2a-Mediated Stress Granule Formation and Propensity to Pulmonary Vascular Disease (2011)
  • Author(s): Sawada H、Alastalo TP, Glotzbach JP, Chan R, Fuchs G, Januszyk M, Lai YJ, Perez VDJ, Kim YM, Wang L, Saito T, Spiekerkoetter E, Gurtner GC, Sarnow P and Rabinovitch M.
  • Organizer: AHA Scientific Session 20113CPR Cournand & Comroe Young Investigator Award Competition
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-11-13
• [Presentation] Reduced BMPR2 increases GM-CSF mRNA translation by inhibiting eIF2α mediated stress granule formation and propensity to pulmonary vascular disease. (2011)
  • Author(s): Hirofumi Sawada
  • Organizer: American Heart Association Scientific Session 20111
  • Place of Presentation: Orlando, FL, USA
• [Book] 小児科診療ガイド (2012)
  • Author(s): 澤田 博文 三谷 義英
  • Total Pages: 5
  • Publisher: 中山書店
• [Book] Nitric oxide in the pathophysiology and treatment of pulmonary hypertension(SBN 980-953-307-704-3)
  • Author(s): Maruyama J, Zhang E, Yokochi A, Sawada H Maruyama K.
  • Publisher: InTech, Pulmonary Hypertension
  • URL: http://dx.doi.org/10.5772/55680