A Nobel Protein TMEM100 and Pulmonary Hypertension and Right-sided Heart Failure.

• Project/Area Number: 25293187
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nara Medical University
• Principal Investigator: SAITO YOSHIHIKO 奈良県立医科大学, 医学部, 教授 (30250260)
• Co-Investigator(Kenkyū-buntansha): ONOUE Kenji 奈良県立医科大学, 医学部第1内科, 助教 (90510173) ; 染川 智 奈良県立医科大学, 医学部, 助教 (90453167)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2015: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
• Keywords: TMEM100 / 肺高血圧 / 右心不全 / BMP9/10 / IP3受容体 / ＧＰＲ78 / ALK1 / 血管新生 / BMP9

Outline of Final Research Achievements

The mechanism for pulmonary arterial hypertension (PAH) and its complication, right-sided heart failure is unknown. Using cDNA array analyses in the right ventricular tissues in the rats with monocrotaline-induced pulmonary hypertension, we have focused TMEM100, which is 20kD protein located in endo-cyto plasmic reticulum. Interestingly, TMEM100 expression is upregulated in cultured human umbilical arterial endothelial cells by BMP9/10, specific ligands for ALK1/BMPR2 receptors, recognized as causative genes for PAH by the linkage analysis in familial PAH. Thus, it is expected that TMEM100 is involved in the pathogenesis of PAH and its complication, right-sided heart failure.
Because of mice lacking the tmem100 gene is embryonic lethal, we generated inducible knockout mice of the tmem100 gene. Unfortunately, in spite of several experimental pulmonary arterial hypertension models, we have not found the evidence that TMEM100 is involved in the pathogenesis of PAH.

Research Products

• [Journal Article] Impairment of endothelial-mesenchymal transformation during atrioventriucular cushion formation in Tmem100 null embryo (2015)
  • Author(s): Mizuta K., Sakabe M., Ioka T., Hashimoto A., Ioka T., Sakai C., Okumura K., Hattammaru M., Fujita M., Araki M., Somekawa S., Saito Y., Nakagawa O
  • Journal Title: Developmental Dynamics Volume: 244 Issue: 1 Pages: 31-42
  • DOI: 10.1002/dvdy.24216
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • NAID: 130005083936
  • Peer Reviewed / Open Access
• [Journal Article] Major Non-Cardiac 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: Circulation Journal Volume: 79 Issue: 4 Pages: 867-872
  • DOI: 10.1253/circj.CJ-14-1111
  • NAID: 130005130262
  • ISSN: 1346-9843, 1347-4820
  • 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 Issue: 1 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: Circulation Journal Volume: 79 Issue: 6 Pages: 1307-1314
  • DOI: 10.1253/circj.CJ-14-1203
  • NAID: 130005073144
  • ISSN: 1346-9843, 1347-4820
  • 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 Issue: 11 Pages: 2871-2881
  • 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: Circulation Journal Volume: 79 Issue: 6 Pages: 1255-1262
  • DOI: 10.1253/circj.CJ-15-0217
  • NAID: 130005073152
  • ISSN: 1346-9843, 1347-4820
  • 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
  • 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 Issue: 3 Pages: 242-242
  • 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 chronic kidney disease (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(2) Issue: 2 Pages: 393-403
  • DOI: 10.1038/ki.2013.339
  • Peer Reviewed / Open Access
• [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: 1-6
  • 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 Issue: 5 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: Internal Medicine Volume: 53 Issue: 4 Pages: 315-319
  • DOI: 10.2169/internalmedicine.53.1386
  • NAID: 130003392649
  • ISSN: 0918-2918, 1349-7235
  • 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: 1-3
  • 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
  • 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(1):e86301 Issue: 1 Pages: 1-1
  • DOI: 10.1371/journal.pone.0086301
  • Peer Reviewed / Open Access
• [Journal Article] The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). (2014)
  • Author(s): Shimamoto K, Hasebe N et al
  • Journal Title: Hypertens Res Volume: 37 Issue: 4 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 Issue: 6 Pages: 001174-001174
  • 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 Issue: 5 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 Issue: 3 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 Issue: 4 Pages: 321-329
  • DOI: 10.1097/mca.0000000000000091
  • Peer Reviewed
• [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: Kid Int. Volume: 85 Pages: 393-403
  • Peer Reviewed
• [Journal Article] Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations. (2013)
  • Author(s): Arimura T, Onoue K, Takahashi-Tanaka Y, Ishikawa T, Kuwahara M, Setou M, Shigenobu S, Yamaguchi K, Bertrand AT, Machida N, Takayama K, Fukusato M, Tanaka R, Somekawa S, Nakano T, Yamane Y, Kuba K, Imai Y, Saito Y, Bonne G, Kimura A.
  • Journal Title: Cardiovasc Res. Volume: 99 Pages: 382-94
  • Peer Reviewed
• [Journal Article] High mean corpuscular volume (MCV) is a new predictor of prognosis in patients with acute decompensated heart failure. (2013)
  • 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: Circ J. Volume: 77 Pages: 2766-71
  • Peer Reviewed
• [Journal Article] Hypertrophic cardiomyopathy and mesenteric venous thrombosis in a patient with Klinefelter syndrome. (2013)
  • Author(s): Okayama S, Uemura S, Saito Y.
  • Journal Title: Int J Cardiol. Volume: 166
  • Peer Reviewed
• [Presentation] Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) Trial Investigators Long-term Use of Low-dose Aspirin Develops Proteinuria in Patients With Diabetes: A Reanalysis of JPAD Study. (2013)
  • Author(s): Okada S, Morimoto T, Ogawa H, Sakuma M, Soejima H, Ohtorii M, Nakayama M, Doi N, Akai Y, Jinnouchi H, Waki M, Sugiyama S, Uemura S, Saito Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, Texas, USA
• [Presentation] Uremic Toxin Aggravates Atherosclerosis by Suppression of Endothelial Soluble Flt-1 Production in CKD. (2013)
  • Author(s): akeda Y, Uemura S, Matsui M, Matsumoto T, Seno A, Okada S, Nishida T, Soeda T, Okayama S, Somekawa S, Watanabe M, Kawata H, Kawakami R, Saito Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, Texas, USA
• [Presentation] Worsening of Renal Function after One Year, Not During Hospitalization, is Stronger Predictor of Prognosis in Patients With ADHF. (2013)
  • Author(s): Ueda T, Kawakami R, Sugawara Y, Matsumoto T, Okada S, Soeda T, Okayama S, Somekawa, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, Texas, USA
• [Presentation] Proximal Stent Edge Location on Thin Cap Fibroatheroma is a Predictor of In-Stent Restenosis -Optical Coherence Tomography Study. (2013)
  • Author(s): Ueda T, Uemura S, Kurokawa M, Sugawara Y, Soeda T, Takeda Y, Watanabe M, Kawata H, Kawakami R, Saito Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, Texas, USA
• [Presentation] Side Branch Complication after Single Stent Crossover Technique: Prediction with Pre-procedural Optical Coherence Tomography Evaluation. (2013)
  • Author(s): Watanabe M, Uemura S, Sugawara Y, Ueda T, Soeda T, Takeda Y, Kawata H, Kawakami R, Saito Y.
  • Organizer: American Heart Association
  • Place of Presentation: Dallas, Texas, USA
• [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/
• [Remarks] 奈良県立医科大学第１内科学教室ホームページ
  • URL: http://www.naramed-u.ac.jp/~1int/