肺高血圧―右心不全発症における新規TMEM100遺伝子の病態生理的意義の解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25293187
• Research Institution: Nara Medical University
• Principal Investigator: 斎藤 能彦 奈良県立医科大学, 医学部, 教授 (30250260)
• Co-Investigator(Kenkyū-buntansha): 尾上 健児 奈良県立医科大学, 医学部, 助教 (90510173)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 肺高血圧 / 右心不全

Outline of Annual Research Achievements

肺高血圧とそれに随伴する右心不全に対する研究の重要性が増している。我々は肺高血圧の原因遺伝子の一つであるALK1/BMPR2受容体複合体の下流で調節されている新規タンパク質Tmem 100の意義の解明を進めてきた。
モノクロタリン誘導性の肺高血圧モデルではTmem 100の肺での発現量は減少していることより肺高血圧の発症に関与している可能性が示唆されていた。
Tmem 100の遺伝子欠損マウスは胎性9.5日で動脈形成不全の為胎生致死であった。そこで、VE cadherin-ER-Cre TgマウスとTmem 100 floxマウスを交配させ誘導型内皮細胞Tmem 100遺伝子欠損マウスを作成し、肺高血圧での意義を解明することが本研究の第１の目的である。また、Tmem 100の心臓発生での意義も合わせて解明することが第２の目的である。

Current Status of Research Progress

4: Progress in research has been delayed.

Reason

１）タモキシフェンで遺伝子欠損を誘導することにより誘導型TMEM遺伝子欠損マウス(c-EC-Tmem100KO)の作成に成功した。このマウスは肺でのTME100の発現が感度以下まで低下していたが、肺高血圧は観察されなかった。
そこで、低酸素刺激による肺高血圧を誘導しc-EC-TMEM100KOがTmem floxと比べて肺高血圧症は増悪していなかった。
２）逆に内皮特異的Tmem 100Tg作成し、低酸素刺激による肺高血圧を誘導したが、Tgと野生型で肺高血圧の程度には差が認められなかった。
上記１）２）の実験からTmem 100の肺高血圧症発症への意義は認められなかった。
３）Tmem 100の胎生期心臓形成における意義を明らかにするため、Tmem100 KOマウス胎仔の心臓形態について詳細に検討した。その結果、胎生9.5-11.5日に生ずる心臓房室管内皮細胞の間葉細胞への分化（Endothelial-Mesenchymal Transformation、EndMT）が、Tmem100欠損によって著しい阻害を受けることが明らかになった（Mizuta et al., 2015）。Tmem100 KOマウス胎仔の房室管内皮においてカルシウムシグナル反応性のNFATc1転写因子核移行が消失していることより、内皮細胞内のカルシウムイオンによるシグナル伝達系が障害されていることを明らかにした。

Strategy for Future Research Activity

当初肺高血圧症に関与するALK1/BMPR2の下流で働く胃D年始の候補としてTmem100の同定に成功したが、Tmem100の遺伝子欠損マウスは胎生致死であった。誘導型Tmem100遺伝子欠損マウスを作成し、低酸素刺激等にても肺高血圧の発症にはTmem100が関与している結果は未だに得られていない。
大きな仮説が実証できないことから研究の当初の予定は進行していない。
しかし、Tmem100はサカナからヒトまで保存されているタンパク質であり、動脈新生に必須のタンパク質であることは証明されている。また、Tmem100が胎生致死する以前に心臓形態を詳細に検討した結果心臓房室管内皮細胞の間葉細胞への分化を障害し心内膜症欠損に関与していることが明らかとなった。
この分子機序を、胎仔心臓房室管のエクスプラント培養系で検討している。
当初の研究計画とは異なるがTmem100の循環器系での意義の解明を継続しTmem100の意義を解明し続けている。

Research Products

• [Journal Article] Impairment of endothelial-mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos. (2015)
  • Author(s): Mizuta K, Sakabe M, Hashimoto A, Ioka T, Sakai C, Okumura K, Hattammaru M, Fujita M, Araki M, Somekawa S, Saito Y, Nakagawa O.
  • Journal Title: Dev Dyn. Volume: 244 Pages: 31-42
  • DOI: 10.1002/dvdy.24216
  • Peer Reviewed / Open Access
• [Journal Article] Proteinuria and Reduced Estimated Glomerular Filtration Rate Are Independent Risk Factors for Contrast-Induced Nephropathy After Cardiac Catheterization. (2015)
  • Author(s): Saito Y, Watanabe M, Aonuma K, Hirayama A, Tamaki N, Tsutsui H, Murohara T, Ogawa H, Akasaka T, Yoshimura M, Sato A, Takayama T, Sakakibara M, Suzuki S, Ishigami K, Onoue K; CINC-J study investigators.
  • Journal Title: Circ J. Volume: 79 Pages: 1624-30
  • DOI: 10.1253/circj
  • Peer Reviewed / Open Access
• [Journal Article] Major noncardiac surgery is a risk factor for rapid hemodynamic progression of non-rheumatic aortic stenosis. (2015)
  • Author(s): Mizuno R, Yamagami S, Higashi T, Nakada Y, Takeda Y, Okayama S, Fujimoto S, Saito Y.
  • Journal Title: Cir J. Volume: 79 Pages: 867-872
  • DOI: 10.1253/circj.CJ-14-1111.
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of coronary artery disease and cardiac morphology and function in patients with hypertrophic cardiomyopathy, using cardiac computed tomography. (2015)
  • Author(s): Okayama S, Soeda T, Kawakami R, Takami Y, Somekawa S, Ueda T, Sugawara Y, Matsumoto T, Sung JH, Nishida T, Uemura S, Saito Y.
  • Journal Title: Heart Vessels. Volume: 30 Pages: 28-35
  • DOI: 10.1007/s00380-013-0452-9.
  • Peer Reviewed / Open Access
• [Journal Article] Plasma Renin Activity Is a Strong and Independent Prognostic Indicator in Patients With Acute Decompensated Heart Failure Treated With Renin-Angiotensin System Inhibitors. (2015)
  • Author(s): Ueda T, Kawakami R, Nishida T, Onoue K, Soeda T, Okayama S, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y.
  • Journal Title: Circ J. Volume: Mar 3 Pages: Epub
  • DOI: 10.1253/circj.CJ-14-1203.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Placental Growth Factor As A Predictor Of Cardiovascular Events In Patients With Chronic Kidney Disease from the Novel Assessment of Risk management for Atherosclerotic diseases in Chronic Kidney Disease (NARA-CKD) Study. (2015)
  • Author(s): Matsui M, Uemura S, Takeda Y, Samejima K, Matsumoto T, Hasegawa A Tsushima H, Hoshino E, Ueda T, Morimoto K, Okamoto K, Okada S, Onoue K, Okayama S, Kawata H, Kawakami R, Maruyama N, Akai Y, Iwano M, Shiiki H, Saito Y, for the NARA-CKD investigators.
  • Journal Title: J Am Soc Nephrol. Volume: Mar 18 Pages: in press
  • DOI: 10.1681/ASN.2014080772.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical Presentation, Management and Outcome of Japanese Patients With Acute Myocardial Infarction in the Troponin Era - Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET). (2015)
  • Author(s): Ishihara M, Fujino M, Ogawa H, Yasuda S, Noguchi T, Nakao K, Ozaki Y, Kimura K, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Tsujita K, Nishimura K, Miyamoto Y; J-MINUET investigators.
  • Journal Title: Circ J. Volume: Apr 24 Pages: Epub
  • DOI: 10.1253/circj.CJ-15-0217.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of cardiac prognosis in hemodialysis patients by using coronary computed tomography angiography and thallium single photon emission computed tomography: a retrospective study (2015)
  • Author(s): Okayama S, Tanaka K, Kawata H, Dote Y, Matsui M, Samejima K, Takeda Y, Uemura S, Saito Y
  • Journal Title: Experimental & Clinical Cardiology. Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] Cardiac amyloidosis incidentally detected using technetium-99m hydroxymethylene diphosphonate bone scintigraphy in a patient with prostate cancer. (2015)
  • Author(s): Okayama S, Sugimoto M, Nakano T, Onoue K, Sakaguchi Y, Uemura S, Saito Y.
  • Journal Title: IJC Heart & Vessels. Volume: 4 Pages: 213-214
  • DOI: 10.1016/j.ijchv.2014.04.010.
  • Peer Reviewed
• [Journal Article] Author's reply.[Cardiomyopathy: progress in diagnosis and treatments. Topics: III. Diagnosis leading to selection of therapy: 2. Biomarker] (2014)
  • Author(s): Horii M, Saito Y.
  • Journal Title: J Cardiol. Volume: 64 Pages: 242
  • DOI: 10.1016/j.jjcc.2014.01.008.
  • Peer Reviewed / Open Access
• [Journal Article] Suppressed Soluble Fms-Like Tyrosine Kinase-1 Production Aggravates Atherosclerosis in CKD : Evaluation by Circulating sFlt-1 Levels after Low-Dose Heparin Injection. (2014)
  • Author(s): Matsui M, Takeda Y, Uemura S, Matsumoto T, Seno A, Onoue K, Tsushima H, Morimoto K, Soeda T, Okayama S, Somekawa S, Samejima K, Kawata H, Kawakami R, Nakatani K, Iwano M, Saito Y,
  • Journal Title: Kidney Int. Volume: 85 Pages: 393-403
  • DOI: 10.1038/ki.2013.339.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Therapeutic Benefits of Tocilizumab Vary in Different Organs of a Patient with AA Amyloidosis. (2014)
  • Author(s): Matsui M, Okayama S, Tsushima H, Samejima K, Kanki T, Hasegawa A, Morimoto K, Akai Y, Takano M, Uemura S, Ohbayashi C, Saito Y.
  • Journal Title: Case Rep Nephrol. Volume: 823093 Pages: Epub
  • DOI: 10.1155/2014/823093.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Atrial Natriuretic Peptide Locally Counteracts the Deleterious Effects of Cardiomyocyte Mineralocorticoid Receptor Activation. (2014)
  • Author(s): Nakagawa H, Oberwinkler H, Nikolaev VO, Gabner B, Umbenauer S, Wagner H, Saito Y, Baba HA, Frantz S, Kuhn M.
  • Journal Title: Circ Heart Fail. Volume: 7 Pages: 814-821
  • DOI: 10.1161/CIRCHEARTFAILURE.113.000885.
  • Peer Reviewed / Open Access
• [Journal Article] Refractory high output heart failure in a patient with primary mitochondrial respiratory chain disease. (2014)
  • Author(s): Nakagawa H, Okayama S, Kamon D, Nakano T, Onoue K, Kawakami R, Horii M, Sakaguchi Y, Uemura S, Takemura G, Saito Y.
  • Journal Title: Intern Med. Volume: 53 Pages: 315-319
  • DOI: 10.2169/internalmedicine.53.1386
  • Peer Reviewed / Open Access
• [Journal Article] Three different morphologies of inferior vena cava thrombosis: case reports. (2014)
  • Author(s): Okayama S, Nakada Y, Uemura S, Saito Y.
  • Journal Title: Case Rep Vasc Med. Volume: 349213 Pages: Epub
  • DOI: 10.1155/2014/349213.
  • Peer Reviewed / Open Access
• [Journal Article] Three different morphologies of inferior vena cava thrombosis (2014)
  • Author(s): Okayama.S, Nakada Y, Uemura S, Saito Y.
  • Journal Title: Case Rep in Vasc Med. Volume: Mar 4 Pages: Epub
  • DOI: 10. 1155/ 2014/ 349213.
  • Peer Reviewed / Open Access
• [Journal Article] Cardiomyopathy: progress in diagnosis and treatments. Topics: III. Diagnosis leading to selection of therapy: 2. Biomarker. (2014)
  • Author(s): Onoue K, Nkano T, Saito Y.
  • Journal Title: Nihon Naika Gakkai Zasshi 103: 345-52, 2014 Volume: 103 Pages: 345-352
  • Peer Reviewed
• [Journal Article] Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. (2014)
  • Author(s): Sakan H, Nakatani K, Asai O, Imura A, Tanaka T, Yoshimoto S, Iwamoto N, Kurumatani N, Iwano M, Nabeshima Y, Konishi N, Saito Y.
  • Journal Title: PLoS One. Volume: 9 Pages: e86301
  • DOI: 10.1371/journal.pone.0086301.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). (2014)
  • Author(s): Shimamoto K, Ando K, et al; Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension.
  • Journal Title: Hypertens Res. 37:253-387, 2014 Volume: 37 Pages: 253-387
  • DOI: 10.1038/hr.2014.20.
  • Peer Reviewed / Open Access
• [Journal Article] Worsening of renal function during 1 year after hospital discharge is a strong and independent predictor of all-cause mortality in acute decompensated heart failure. (2014)
  • Author(s): Ueda T, Kawakami R, Sugawara Y, Okada S, Nishida T, Onoue K, Soeda T, Okayama S, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y.
  • Journal Title: J Am Heart Assoc. Volume: 3 Pages: 001174
  • DOI: 10.1161/JAHA.114.001174.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Colocalization of thin-cap fibroatheroma and spotty calcification is a powerful predictor of procedure-related myocardial injury after elective coronary stent implantation. (2014)
  • Author(s): Ueda T, Uemura S, Watanabe M, Sugawara Y, Soeda T, Okayama S, Takeda Y, Kawata H, Kawakami R, Saito Y.
  • Journal Title: Coron Artery Dis. 25:384-91, 2014. Volume: 25 Pages: 384-391
  • DOI: 10.1097/MCA.0000000000000114.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Noncardiovascular death, especially infection, is a significant cause of death in elderly patients with acutely decompensated heart failure. (2014)
  • Author(s): Ueda T, Kawakami R, Horii M, Sugawara Y, Matsumoto T, Okada S, Nishida T, Soeda T, Okayama S, Somekawa S, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y.
  • Journal Title: J Card Fail.20:174-80, 2014 Volume: 20 Pages: 174-180
  • DOI: 10.1016/j.cardfail.2013.12.007.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Side branch complication after a single-stent crossover technique: prediction with frequency domain optical coherence tomography. (2014)
  • Author(s): Watanabe M, Uemura S, Sugawara Y, Ueda T, Soeda T, Takeda Y, Kawata H, Kawakami R, Saito Y.
  • Journal Title: Coron Artery Dis. 25: 321-9, 2014 Volume: 25 Pages: 321-329
  • DOI: 10.1097/MCA.0000000000000091.
  • Peer Reviewed
• [Remarks] 奈良県立医科大学第１内科ホームページ
  • URL: http://www.naramed-u.ac.jp/~1int/