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室原 豊明 Toyoaki Murohara名古屋大学大学院医学系研究科循環器内科学・教授・医学博士


専門分野

循環器内科学

略歴

1985年3月
熊本大学医学部 卒業
1988年4月
熊本大学大学院 医学系研究科 内科系 入学
(1988年6月〜1989年3月 国内留学 東京大学医学部薬理学教室)
1992年3月
熊本大学大学院・医学系研究科・内科系 卒業 (医学博士)
1993年9月
米国ジェファーソン医科大学、生理学教室・研究員
1996年3月
米国タフツ大学セントエリザベス医療センター心臓内科・研究員
1997年7月
久留米大学医学部第三内科・助手
1998年8月
久留米大学循環器病研究所・医学部第三内科・講師(兼任)
2002年6月
名古屋大学大学院医学系研究科・分子総合医学専攻・病態内科学講座・器官制御内科学(現 循環器内科学)・教授 現在に至る

研究課題名

血管神経再生制御による腫瘍増殖・動脈硬化抑制の試み

これまでの成果と今後の展望

Girdin/GIVは低分子量Gタンパク質のR-Rasを介してVE-cadherinの細胞内輸送に関与し、血管内皮細胞の透過性を制御する 

A. 背景・研究目的
 血管透過性は血管内皮細胞間の細胞間の結合構造によって制御される。血管透過性の亢進はさまざまな病的状態に関与しているといわれている。しかし、細胞外の刺激がどのようにして内皮細胞間の結合を制御するのかは明らかではない。血管内皮細胞間の結合は、adherens junction(AJ)とtight junction(TJ)という少なくとも2つの異なる構造により制御されている。VE-cadherinは血管内皮細胞に限局して発現しているカドヘリン・ファミリーの分子でありAJの形成に重要である。VEGFなどの細胞外からの刺激は、VE-cadherinやその結合タンパクの機能の調節を通じて、血管透過性を亢進させることが知られている。これらの血管透過性亢進因子に曝露されている時だけではなく、静止状態にある内皮細胞でも、AJは持続的にリモデリングしていることが判明している。このリモデリングには、VE-cadherinのエンドサイトーシスとリサイクリングが関与していると考えられている。今回我々は、アクチン結合分子GirdinがVE-cadherinの細胞内輸送の調節に関与し、血管透過性を制御していることを発見した。

B. 研究成果
図A、B、Cに示すように、GirdinをノックダウンしたHUVECではVEGFで生じるVE-cadherinのエンドサイトーシス、AJの解離、FITC-dextranの透過性は減少していた、さらに、GirdinはVE-cadherin、clathrin heavy chainと複合体を形成していた。これらのことから、GirdinはVE-cadherinのエンドサイトーシスに関与していることが示唆された。さらに、我々は血管内皮細胞の安定性を惹起すると報告されている低分子量GタンパクであるR-Rasに着目した。R-RasはVEGF刺激で活性化されGirdinと複合体を形成することが判明した。また、R-RasはGirdinとVE-cadherinの複合体形成を制御していることが判明した(図D、E、F、G)。GirdinはconfluentのHUVECでは細胞間接着部位近傍のアクチン線維に存在していたが、R-Rasのノックダウンにより、この局在は消失した(図I)。一方、R-Rasのノックダウンで亢進した血管透過性はGirdinを同時にノックダウンすることで正常化した。
図Jにこれらの実験から推測されるワーキングモデルを示す。VEGF刺激下でR-Rasは活性化され、GirdinとVE-cadherinは複合体を形成する。活性化したR-Ras/Girdinと結合した細胞内のVE-cadherinはリサイクリングされ、再び細胞膜上に輸送される。しかし、R-Rasが不活性化されGirdinから離れたVE-cadherinは、リゾソームによるタンパク分解経路にリクルートされる可能性が考えられた。

主要研究業績

  1. Uchida Y, Takeshita K, Yamamoto K, Kikuchi R, Nakayama T, Nomura M, Cheng XW, Egashira K, Matsushita T, Nakamura H, Murohara T: Stress Augments Insulin Resistance and Prothrombotic State: Role of Visceral Adipose-Derived Monocyte Chemoattractant Protein-1. Diabetes, in press (2012)
  2. Ishii H, Kumada Y, Takahashi H, Toriyama T, Aoyama T, Tanaka M, Yoshikawa D, Hayashi M, Kasuga H, Yasuda Y, Maruyama S, Matsubara T, Matsuo S, Murohara T: Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis. Diabetologia, in press (2012)
  3. Cheng XW, Shi GP, Kuzuya M, Sasaki T, Okumura K, Murohara T: Role for cysteine protease cathepsins in heart disease: focus on biology and mechanisms with clinical implication. Circulation, 125, 1551-1562 (2012)
  4. Murase T, Hattori T, Ohtake M, Nakashima C, Takatsu M, Murohara T, Nagata K: Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z-Leprfa/Leprfa Rats as a New Animal Model of Metabolic Syndrome. Hypertension, 59, 694-704 (2012)
  5. Maruyama S, Shibata R, Kikuchi R, Izumiya Y, Rokutanda T, Araki S, Kataoka Y, Ohashi K, Daida H, Kihara S, Ogawa H, Murohara T, Ouchi N: Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism. J Biol Chem, 287, 408-417 (2012)
  6. Shimano M, Ouchi N, Nakamura K, van Wijk B, Ohashi K, Asaumi Y, Higuchi A, Pimentel DR, Sam F, Murohara T, van den Hoff MJ, Walsh K: Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci U S A, 108, E899-906 (2011)
  7. Cheng XW, Huang Z, Kuzuya M, Okumura K, Murohara T: Cysteine protease cathepsins in atherosclerosis-based vascular disease and its complications. Hypertension, 58, 978-986 (2011)
  8. Enomoto T, Ohashi K, Shibata R, Higuchi A, Maruyama S, Izumiya Y, Walsh K, Murohara T, Ouchi N: Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism. J Biol Chem, 286, 34552-34558 (2011)
  9. Maruyama S, Shibata R, Ohashi K, Ohashi T, Daida H, Walsh K, Murohara T, Ouchi N: Adiponectin ameliorates doxorubicin-induced cardiotoxicity through Akt protein-dependent mechanism. J Biol Chem, 286, 32790-32800 (2011)
  10. Ishii M, Shibata R, Numaguchi Y, Kito T, Suzuki H, Shimizu K, Ito A, Honda H, Murohara T: Enhanced angiogenesis by transplantation of mesenchymal stem cell sheet created by a novel magnetic tissue engineering method. Arterioscler Thromb Vasc Biol, 31, 2210-2215 (2011)
  11. Tsuji Y, Hojo M, Voigt N, El-Armouche A, Inden Y, Murohara T, Dobrev D, Nattel S, Kodama I, Kamiya K: Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm. Circulation, 123, 2192-2203 (2011)
  12. Cheng XW, Song H, Sasaki T, Hu L, Inoue A, Bando YK, Shi GP, Kuzuya M, Okumura K, Murohara T: Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Hypertension, 57, 981-989 (2011)
  13. Miyake H, Maeda K, Asai N, Shibata R, Ichimiya H, Isotani-Sakakibara M, Yamamura Y, Kato K, Enomoto A, Takahashi M, Murohara T: The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury. Circ Res, 108, 1170-1179 (2011)
  14. Kikuchi R, Takeshita K, Uchida Y, Kondo M, Cheng XW, Nakayama T, Yamamoto K, Matsushita T, Liao JK, Murohara T: Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF. Lab Invest, 91, 691-703 (2011)
  15. Matsushita E, Asai N, Enomoto A, Kawamoto Y, Kato T, Mii S, Maeda K, Shibata R, Hattori S, Hagikura M, Takahashi K, Sokabe M, Murakumo Y, Murohara T, Takahashi M: Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells. Mol Biol Cell, 22, 736-747 (2011)
  16. Morimoto Y, Kureishi Bando Y, Shigeta T, Monji A, Murohara T: Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53. J Atheroscler Thromb, 18, 200-208 (2011)
  17. Cheng XW, Kuzuya M, Sasaki T, Inoue A, Hu L, Song H, Huang Z, Li P, Takeshita K, Hirashiki A, Sato K, Shi GP, Okumura K, Murohara T: Inhibition of mineralocorticoid receptor is a renoprotective effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin. J Hypertens, 29, 542-552 (2011)
  18. Kubota R, Numaguchi Y, Ishii M, Niwa M, Okumura K, Naruse K, Murohara T: Ischemia-induced angiogenesis is impaired in aminopeptidase A deficient mice via down-regulation of HIF-1α. Biochem Biophys Res Commun, 402, 396-401 (2010)
  19. Suzuki H, Shibata R, Kito T, Ishii M, Li P, Yoshikai T, Nishio N, Ito S, Numaguchi Y, Yamashita JK, Murohara T, Isobe K: Therapeutic angiogenesis by transplantation of induced pluripotent stem cell-derived Flk-1 positive cells. BMC Cell Biol, 11, 72 (2010)
  20. Murakami R, Murakami H, Kataoka H, Cheng XW, Takahashi R, Numaguchi Y, Murohara T, Okumura K: Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes. Life Sci, 87, 495-500 (2010)
  21. Cheng XW, Kuzuya M, Kim W, Song H, Hu L, Inoue A, Nakamura K, Di Q, Sasaki T, Tsuzuki M, Shi GP, Okumura K, Murohara T: Exercise training stimulates ischemia-induced neovascularization via phosphatidylinositol 3-kinase/Akt-dependent hypoxia-induced factor-1 alpha reactivation in mice of advanced age. Circulation, 122, 707-16 (2010)
  22. Li P, Shibata R, Maruyama S, Kondo M, Ohashi K, Ouchi N, Murohara T: Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway. Am J Physiol Endocrinol Metab, 299, E560-6 (2010)
  23. Nishizawa T, Cheng XW, Jin Z, Obata K, Nagata K, Hirashiki A, Sasaki T, Noda A, Takeshita K, Izawa H, Shi GP, Kuzuya M, Okumura K, Murohara T: Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats. J Hypertens, 28, 1515-1526 (2010)
  24. Kataoka H, Murakami R, Numaguchi Y, Okumura K, Murohara T: Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial nitric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells. Eur J Pharmacol, 636, 36-41(2010)
  25. Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K: DRR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun, 394, 829-35 (2010)
  26. Kondo K, Shibata R, Unno K, Shimano M, Ishii M, Tetsutaro K, Shintani S, Walsh K, Ouchi N, Murohara T. Impact of a Single Intracoronary Administration of Adiponectin on Myocardial Ischemia/Reperfusion Injury in a Pig Model. Circ Cardiovasc Interv, 3, 166-173 (2010)
  27. Uetani T, Amano T, Kunimura A, Kumagai S, Ando H, Yokoi K, Yoshida T, Kato B, Kato M, Marui N, Nanki M, Matsubara T, Ishii H, Izawa H, Murohara T. The Association Between Plaque Characterization by CT Angiography and Post-Procedural Myocardial Infarction in Patients With Elective Stent Implantation. J Am Coll Cardiol Cardiovasc Imaging, 3, 19-28 (2010)
  28. Kondo K, Shintani S, Shibata R, Murakami H, Murakami R, Imaizumi T, Kitagawa S, Murohara T. Implantation of adipose-derived regenerative cells enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol, 29, 61-66 (2009)
  29. Kondo M, Shibata R, Miura R, Shimano M, Kondo K, Li P, Ohashi T, Kihara S, Maeda N, Walsh K, Ouchi N, Murohara T. Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of eNOS. J Biol Chem, 284, 1718-1724 (2009)
  30. Mori K, Amano M, Takefuji M, Kato K, Morita Y, Nishioka T, Matsuura Y, Murohara T, Kaibuchi K. Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. J Biol Chem, 284, 5067-5076 (2009)
  31. Morikawa S, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Morita Y, Numaguchi Y, Okumura K, Murohara T. Renal protective effects and the prevention of contrast-induced nephropathy by atrial natriuretic peptide. J Am Coll Cardiol, 53, 1040-1046 (2009)
  32. Uetani T, Amano T, Kumagai S, Ando H, Yokoi K, Yoshida T, Kato B, Kato M, Marui N, Nanki M, Matsubara T, Ishii H, Izawa H, Murohara T. Intracoronary electrocardiogram recording with a bare-wire system: perioperative ST-segment elevation in the intracoronary electrocardiogram Is associated with myocardial injury after elective coronary stent implantation. JACC Cardiovasc Interv, 2, 127-135 (2009)
  33. Numaguchi Y, Ishii M, Kubota R, Morita Y, Yamamoto K, Matsushita T, Okumura K, Murohara T. Ablation of Angiotensin IV Receptor Attenuates Hypofibrinolysis via PAI-1 Downregulation and Reduces Occlusive Arterial Thrombosis. Arterioscler Thromb Vasc Biol, 29, 2102-2108 (2009)
  34. Li P, Shibata R, Unno K, Shimano M, Furukawa M, Ohashi T, Cheng X, Nagata K, Ouchi N, Murohara T. Evidence for the importance of adiponectin in the cardioprotective effects of pioglitazone. Hypertension, 55, 69-75 (2009)
  35. Ishii H, Toriyama T, Aoyama T, Takahashi H, Amano T, Hayashi M, Tanaka M, Kawamura Y, Yasuda Y, Yuzawa Y, Maruyama S, Matsuo S, Matsubara T, Murohara T. Prognostic values of C-reactive protein levels on clinical outcome after implantation of sirolimus-eluting stents in patients on hemodialysis. Circ Cardiovasc Interv, 2, 513-518 (2009)
  36. Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, Murohara T. Role of bradykinin, nitric oxide and angiotensin II type 2 receptor in imidapril-induced angiogenesis. Hypertension, 51, 252-258 (2008)
  37. Amano T, Matsubara T, Uetani T, Nanki M, Marui N, Kato M, Yoshida T, Arai K, Yokoi K, Ando H, Kumagai S, Ishii H, Izawa H, Hotta N, Murohara T. Abnormal glucose regulation is associated with lipid rich coronary plaque: relationship to insulin resistance JACC Cardiovasc Imaging, 1, 39-45 (2008)
  38. Kitamura T, Asai N, Enomoto A, Maeda K, Kato T, Ishida M, Jiang P, Watanabe T, Usukura J, Kondo T, Costantini F, Murohara T, Takahashi M. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat Cell Biol, 10, 329-337 (2008)
  39. Sugiura T, Kondo T, Kureishi-Bando Y, Numaguchi Y, Yoshida O, Dohi Y, Kimura G, Ueda R, Rabelink TJ, Murohara T. Nifedipine improves endothelial function: role of endothelial progenitor cell. Hypertension, 52, 491-498 (2008)
  40. Ishii H, Amano T, Matsubara T, Murohara T. Pharmacological intervention for prevention of left ventricular remodeling and improving prognosis in myocardial infarction. Circulation, 118, 2710-2718 (2008)
  41. Nakamura T et al. Significance and Therapeutic Potential of Endothelial Progenitor Cell Transplantation in a Cirrhotic Liver Rat Model. Gastroenterology 133: 91-107 (2007)
  42. Cheng XW et al. Mechanisms underlying the impairment of ischemia-induced neovascularization in MMP-2-deficient mice. Circ. Res. 100: 904-913 (2007)
  43. Numaguchi Y et al. The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction. Circulation 114: I114-I119 (2006)
  44. Shintani S et al. Synergistic effect of combined intramyocardial CD34 cells and VEGF-2 gene therapy post-myocardial infarction. Nature Clin. Pract. Cardiovasc. Med. 3: S123-S128 (2006)
  45. Egami K et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J. Clin. Invest. 112: 67-75 (2003)
  46. Tateishi-Yuyama E et al. for the Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360: 427-435 (2002)
  47. Sasaki K et al. Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis. J Clin Invest. 109: 603-611 (2002)
  48. Kamihata H et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104: 1046-1052 (2001)
  49. Shintani S et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103: 2776-2779 (2001)
  50. Shintani S et al. Augmentation of postnatal neovascularization with autologous bone marrow transplantation. Circulation 103: 897-903 (2001)
  51. Murohara T et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 105: 1527-1536 (2000)
  52. Murohara T et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 101: 2567-2578 (1998)
  53. Murohara T et al. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 97: 99-107 (1998)
  54. Murohara T et al. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nature Med. 3: 879-886 (1997)
  55. Asahara T et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964-967 (1997)
  56. Buerke M et al. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia and reperfusion. Proc. Natl. Acad. Sci. USA. 92: 8031-8035 (1995)

受賞

Irvine H. Page Award. American Heart Association (AHA), Annual Scientific Sessions 1997, November 9-12,1997, Orlando, Florida. Title: Reciprocal relationship between vascular endothelial growth factor and nitric oxide in the regulation of endothelial integrity.

Young Investigators Award, American College of Cardiology, The 49th Annual Scientific Sessions. March 12-15, 2000, Anaheim, CA. Title: Augmentation of postnatal neovascularization by transplantation of cord blood-derived endothelial progenitor cells.

Press Conference

American Heart Association (AHA), Scientific Sessions 1999, November 7-10, 1999. Atlanta, GA. Murohara T. Heterologous transplantation of human cord blood-derived endothelial progenitor cells participate in postnatal angiogenesis in vivo. CNN, BBC On line. http://news.bbc.co.uk/1/hi/health/510072.stm

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