DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

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Research Units

Vascular Molecular Pathophysiology & Translational Research Unit


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menu Research Outline Main Research Themes and Relevant Publications Principle Investigator of the group Staff and Research Focus

Main Research Themes and Relevant Publications


  1. Translational research of anti-inflammatory (anti-MCP-1, anti-NF-κB) therapies for intractable cardiovascular diseases
  2. Creation and clinical application of advanced nanomedicine by integrated nano-biomedical engineering

1. Translational research of anti-inflammatory (anti-MCP-1, anti-NF-κB) therapies for intractable cardiovascular diseases


Based on the findings obtained from the research conducted so far, we hypothesized that “inflammation” plays a central role in the molecular pathogenesis of arteriosclerotic diseases, and devoted our efforts to test this hypothesis.

変異型MCP-1(7ND)遺伝子導入による抗MCP-1遺伝子治療戦略

As a result, we identified monocyte chemoattractant protein-1 (MCP-1), a monocyte/macrophage chemokine as the key molecule. We found that if we inhibit the function of MCP-1 (anti-MCP-1 gene therapy) or inhibit MCP-1 expression (such as NF-κB inhibition, and vascular protection by ARB, statin and calcium antagonist), inflammation is controlled, and this results in the prevention of arteriosclerotic disease (restenosis or plaque instability) and hypertensive remodeling.


抗MCP-1遺伝子治療による再狭窄・動脈硬化の抑制 再狭窄・動脈硬化の分子機構におけるMCP-1の中心的役割(炎症仮説の証明)

Monocyte Chemoattractant Protein-1(MCP-1)の分子病態的意義We further demonstrated that MCP-1 not only acts simply as a chemokine, but also plays an important role in the progression of cardiovascular disease to organ failure. This knowledge was derived from our findings that (1) MCP-1 receptors are expressed and function not only in leukocytes but also in a variety of cells (including the endothelium, smooth muscles, fibroblasts, myocardium, adipose cells, cancer cells and central neurons); (2) overexpression of MCP-1 results in organ fibrosis, tumor angiogenesis, heart failure, ischemia/reperfusion, and posttransplant arteriosclerosis; and (3) Inhibition of MCP-1 delays the development and progression of diseases. Many institutions have also reported that MCP-1 is a clinical marker for cardiovascular disease and organ failure.
Next, as the second goal, we aimed at “developing effective and safe method to inhibit MCP-1 function as the innovative next generation medicine based on new concept”. We adopted two novel approaches. One is the mutated MCP-1 gene (7ND) that encodes dominant-negative inhibition of MCP-1. Another approach is nuclear factor-κB (NF-κB), an important transcription factor that inhibits the expression of important inflammatory cytokines including MCP-1. Although the details will be omitted here, our studies have demonstrated that these anti-inflammatory therapeutic strategies effectively inhibit cardiovascular pathologies and organ failure. 
http://hyoka.ofc.kyushu-u.ac.jp/search/faculty2_j.cgi?ID=K001970


In addition, we also conducted safety studies and reported that 7ND gene therapy and NF-κB decoy produce no clinically significant toxicity (Ministry of Health, Welfare and Labor scientific research grant report and others). To promote clinical application of these basic study results, we filed for clinical trial of gene therapy and conducted clinical studies of administrating NF-κB decoy in coronary arterial wall.

As a part of the development of advanced medicine, we were the first in the world to conduct peripheral blood endothelial progenitor cell therapy for severe lower limb ischemia caused by arteriosclerosis obliterans (collaborative research with Second Department of Internal Medicine, formerly Department of Blood Transfusion). We conducted the same cell therapy in patients with severe myocardial ischemia caused by ischemic diseases. We also started a feasibility study on the use of excimer laser angioplasty for arteriosclerosis obliterans as well as coronary stenotic or occlusive lesions.

http://www.med.kyushu-u.ac.jp/cardiol/

Importance of translation research (clinical application of basic research results = from bench to bedside research)

Development of innovative medicinal drugs and medical devices that may lead to the conquer of intractable diseases such as cancers, heart diseases and cerebrovascular diseases not only contributes to upgrading the standards of health insurance medical care for the Japanese people, but also plays an important role in the international society. For this reason, technological development toward their practical application is essential, and basic research that provides its foundation is becoming increasingly important.

In the field of advanced medical research in Japan, while increasing achievements have been obtained in the invention of new concepts and technologies that are anticipated to revolutionize the future medical care (basic research achievements that forms the foundation of translation research), little efforts are being made to put these achievements into practical use. In Japan, the research grants from pharmaceutical industries are biased toward studies (such as clinical trials) before practical application of a product or procedure, and insufficient investments are being made on research to study the feasibility of practical application of basic research achievements. In addition, in the development of medical devices, most companies do not have their own system that manages the research and development system.

Therefore, basic research that potentially leads to the development of innovative drugs and medical devices aiming at improving the health care standard, as well as basic research that contributes to intellectual assets such as patents are promoted as a national policy. An example is translational research with the goal to develop innovative medicines or medical devices (such as gene therapy, nanomedicine and molecular imaging) based on novel mechanisms of action or concepts.

If the world-standard medical technologies and medical devices invented in Japan become widely used in the world, we can expect the global availability of high-efficacy, low-adverse effect, minimally invasive medicine that facilitates early social rehabilitation and improves survival. Through the naissance of “global standard” medical care with international competitive power, the new medical industries will generate employment, which will contribute greatly to strengthening the competitiveness of the Japanese industry.

Basic research outcomes that form the basis of translational research are defined as follows: treatment technologies and diagnostic technologies that can potentially be translated to practical use in the clinical setting, and basic patents of drugs or advanced medical technologies filed by researchers which can be applied to practical use.

Clinical application (practical use) which is the goal of translational research is defined as follows: exploratory clinical research and research related to clinical peripheral technology of advanced medical technology in order to increase the opportunity of supplying useful medicinal drugs and medical technology for clinical use.


Relevant Publications (major publications from 2000)
  1. Usui M, Egashira K, Tomita H, Koyanagi M, Katoh M, Shimokawa H, Takeya M, Yoshimura T, Takeshita A: Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by blockade of nitric oxide synthesis. Circulation 2000; 101(3): 305-310.
  2. Koyanagi M, Egashira K, Kitamoto S, Ni W, Shimokawa H, Takeya M, Yoshimura T, Takeshita A: Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis in rats. Circulation 2000; 102(18): 2243-2248.
  3. Kitamoto S, Egashira K, Kataoka C, Koyanagi M, Katoh M, Shimokawa H, Morishita R, Kaneda Y, Sueishi K, Takeshita A: Increased activity of nuclear factor kB participates to cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis in rats. Circulation 2000; 102(7): 806-812.
  4. Egashira K, Koyanagi M, Kitamoto S, Ni W, Kataoka C, Morishita R, Kaneda Y, Nishida K, Sueishi K, Takeshita A: Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in ratsvlockade of MCP-1 activity following intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis. FASEB J 2000; 14(13): 1974-1978.
  5. 江頭健輔:炎症制御による血管病の遺伝子治療. 血管医学 2000;1(2):47-54
  6. 江頭健輔:血管医学研究の現在と未来. 血管医学 2000;1:51-58
  7. Ni WH, Egashira K, Kitamoto S, Kataoka C, Koyanagi M, Inoue S, Imaizumi K, Akiyama C, Nishida K, Takeshita A: New Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Inhibits Atherosclerosis in ApoE-knockout Mice. Circulation 2001; 103(16): 2096-2101.
  8. 江頭健輔他:抗MCP-1遺伝子治療の安全性をカニクイザルで確認. 日経バイオテク 2001;1月号:6
  9. Egashira K, Zhao QW, Kataoka C, Ohtani K, Usui M, Charo IF, Nishida K, Inoue S, Katoh M, Ichiki T, Takeshita A: Importance of Monocyte Chemoattractant Protein-1 Pathway in Neointimal Hyperplasia After Peri-arterial Injury in Mice and Monkeys. Circulation Research 2002; 90:1167-1172.
  10. Usui M, Egashira K, Ohtani K, Kataoka C, Ishibashi M, Hiasa K, Katoh M, Zhao QW, Kitamoto S, Takeshita A: Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Inhibits Restenotic Changes (Neointimal Hyperplasia) After Balloon Injury in Rats and Monkeys. FASEB J 2002; 16(13): 1838-1840.
  11. Monkeys. FASEB J 2002; 16(13): 1838-1840.
  12. Inoue S, Egashira K, Ni WH, Kitamoto S, Usui M, Otani K, Ishibashi M, Hiasa K, Nishida K Takeshita A: Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E-Knockout Mice. Circulation 2002; 106:2700-2706.
  13. 江頭健輔:抗MCP-1遺伝子治療で再狭窄や動脈硬化抑制に新たな戦略を循環器科医師向けのニューズレター エビデンス 日経メディカル開発 2002;Jun
  14. 北本史朗, 江頭健輔:冠インターベンション後再狭窄に対する遺伝子治療. Bio Clinica 臨時増刊号 2002;17(7): 48-53
  15. 江頭健輔, 北本史朗:血管疾患 -抗MCP-1遺伝子治療法- 医学のあゆみ 2002;203(5):349-355
  16. Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, Wen J, Egashira K, Takeshita A: Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2003; 108:2134-2140.
  17. 北本史朗, 江頭健輔:血管再狭窄に対する抗MCP-1遺伝子治療法. 循環器科 2003;53(5):400-406
  18. 北本史朗, 江頭健輔:炎症性疾患に効果のある遺伝子治療 -抗MCP-1遺伝子治療戦略- BIO INDUSTRY 2003;20(10):44-53
  19. Ni W, Kitamoto S, Ishibashi M, Usui M, Inoue S, Hiasa K, Zhao Q, Nishida K, Takeshita A Egashira K: Monocyte Chemoattractant Protein-1 is an essential inflammatory mediator in angiotensin II-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscl Throm Vas Biol 2004;24:534-539.
  20. Ohtani K, Egashira K, Usui M, Ishibashi M, Hiasa K-I, Zhao Q, Aoki M, Kaneda Y, Morishita R, Takeshita A: Inhibition of neointimal hyperplasia after balloon injury by cis-element decoy' of early growth response gene-1 in hypercholesterolemic rabbits. Gene Ther. 2004; 11(2): 126-132.
  21. Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K, Ishida Y, Kondo T, Hiroyuki H, Ishiwata Y, Mukaida N, Tomosugi N,Matsushima K, Egashira K, Yokoyama H: Gene therapy via blockade of MCP-1 for renal fibrosis. J Am Soc Nephrol 2004; 15(4): 940-948.
  22. Ohtani K, Usui M, Nakano K, Kohjimoto Y, Kitajima S, Hirouchi Y, Li X, Kitamoto S, Takeshita A, Egashira K.: Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Reduces Experimental In-Stent Restenosis in Hypercholesterolemic Rabbits and Monkeys. Gene Therapy 2004:11:1273-1282.
  23. Inoshima I, Kuwano K, Hamada N, Hagimoto N, Yoshimi M, Maeyama T, Takeshita A, Kitamoto S, Egashira K, Hara N: Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 2004; 286(5): L1038-1044.
  24. Kitamoto S,Nakano k, Hirouchi Y, Kohjimoto Y, Kitajima S, Usui M, Inoue S, Egashira K: Cholesterol-Lowering Independent Regression and Stabilization of Atherosclerotic Lesions by Pravastatin and by Antimonocyte Chemoattractant Protein-1 Therapy in Nonhuman Primates. Arterioscler Thromb Vasc Biol. 2004; 24:1522-1528.
  25. Saiura A, Sata M, Hiasa K, Kitamoto S, Washida M, Egashira K, Nagai R, Makuuchi M: Antimonocyte Chemoattractant Protein-1 Gene Therapy Attenuates Graft Vasculopathy. Arterioscler Thromb Vasc Biol. 2004 ; 24: 1886-1890.
  26. Shimizu S, Nakashima H, Masutani K, Inoue K, Miyake K, Akahoshi M, Tanaka Y, Egashira K, Hirakata H, Otsuka T, Harada M: Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice. Rheumatology 2004; 43(9): 1121-1128.
  27. Suzuki J, Ito H, Inoue s, Gotoh R, Morishita R, Egashira K, Isobe M: Initial clinical cases of the use of a NF-κB decoy at the site of coronary stenting for the prevention of restenosis. Circulation J 2004; 68 (3): 270-271
  28. Tsuruta S, Nakamuta M, Enjoji M, Katoh K, Hiasa K, Egashira K, Nawata H: Anti-monocyte chemoattractant protein-1 gene therapy prevents dimethylnitrosamine-induced hepatic fibrosis in rats. Int J Mol Med. 2004; 14(5): 837-842.
  29. Kumai Y, Ooboshi H, Takada J, Kamouchi M, Kitazono T, Egashira K, Ibayashi S, Iida M: Anti-monocyte chemoattractant protein-1 gene therapy protects against focal brain ischemia in hypertensive rats. J Cereb Blood Flow Metab. 2004;24(12): 1359-1368.
  30. 江頭健輔:血管医学の新展開 -ニューパラダイムの構築から治療開発へ- 羊土社 実験医学 2004;22(8):84(1106)-88(1110)
  31. 北本史朗, 江頭健輔:動脈硬化・再狭窄の機序におけるMCP-1の役割-炎症仮説の証明 羊土社 実験医学 2004;22(8):89(1111)-95(1117)
  32. Goser S, Ottl R, Brodner A, Dengler TJ, Egashira K, Katus and Kaya Z. Critical Role for MCP-1 and MIP-1a in Induction of Experimental Autoimmune Myocarditis (EAM) and Effective Anti-MCP-1 Gene Therapy. Circulation 2005; 112: 3400 - 3407.
  33. Zhao HF, Ito T, Gibo J, Kawabe K, Oono T, Kaku T, Arita Y, Zhao QW, Usui M, Egashira K, Nawata H. Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Gut. 2005; 54(12): 1759-1767.
  34. 江頭健輔:抗炎症による再狭窄予防対策-遺伝子溶出ステントによる次世代血管内医療システムの開発- 2005;日本循環器学会専門医誌 循環器専門医13(2):289-296
  35. Schepers A, Eefting D, Bonta PI, Grimbergen JM, de VVries MR, vanWeel V, de Vries CJ, Egashira K, van Bockel JH, Quax PH: Anti-MCP-1 gene Therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in citro and in vivo. Arterioscler Thromb Vasc Biol.2006; 26(9): 2063-9.
  36. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M: MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006; 116(6): 1494-505.
  37. Ohtani K, Egashira K, Nakano K, Zhao G, Funakoshi K, Ihara Y, Sunagawa K: Stent-based local delivery of nuclear factor-kB decoy attenuates in-stent restenosis in hypercholesterolemic rabbits. Circulation 2006; 114(25):2773-2779.
  38. 船越公太, 江頭健輔:ステント内再狭窄(動脈硬化の病態基盤)循環器科 2006;59(3):147-153
  39. Takewaki H, Egashira K, Kimura S, Nishida T, Morita S, Tominaga R: Blockade of Monocyte Chemoattractant Protein-1 by Adenoviral Gene Transfer Inhibits Experimental Vein Graft Neointimal Formation. J Vasc Surg. 2007; 45: 1236-43.

 


  1. Translational research of anti-inflammatory (anti-MCP-1, anti-NF-κB) therapies for intractable cardiovascular diseases
  2. Creation and clinical application of advanced nanomedicine by integrated nano-biomedical engineering

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