DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

JAPANESE
font size
font size_s
font size_m
font size_l
color
Research Units

Vascular Molecular Pathophysiology & Translational Research Unit


To Japanese version on this page

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

Research Outline


Molecular Mechanism of Ischemic Heart Diseases: Basic and Clinical Research on the Role of Vascular Endothelial Dysfunction

In a miniature pig model of coronary spasm and in patients with vasospastic angina, we elucidated the role of endothelial dysfunction in the development of spasm (Outstanding Young Investigator’s Award from the Japanese Circulation Society; published in J Clin Invest). Furthermore we demonstrated for the first time in the world that endothelial dysfunction is associated with the pathogenesis of angina pectoris and that coronary risk factors are involved in the pathogenesis (Most Outstanding Young Investigator’s Award from the Japan Arteriosclerosis Society; published in N Engl J Med, J Clin Invest, Lancet and Circulation). We were also the first to report that cholesterol-lowering therapy using statin improves the endothelial function of coronary artery (CPIS Award from the Japanese Circulation Society; published in Circulation). These achievements have made important contribution in the elucidation of “the roles of endothelial cells” and are recognized worldwide.

Molecular Mechanism of Vasospastic Angina: Elucidation of the Intracellular Calcium Kinetics

As a research fellow at the Department of Cardiovascular Medicine of Harvard Medical School Beth Israel Hospital, the lead researcher Kensuke Egashira was in charge of one area of the NIH Program Project Grant. This research demonstrated that an increase in intracellular calcium is essential in the pathogenesis of vasospasm (two reports in J Clin Invest).

Creation of Original Gene Therapy and Cell Therapy Based on Known Molecular Mechanisms of Arteriosclerotic Disease

From the research of the molecular mechanisms of arteriosclerotic diseases, we have demonstrated that monocyte chemoattractant protein-1 (MCP-1) is the key molecule (published in J Clin Invest, Circulation, others), and independently developed the new anti-MCP-1 gene therapy. We were the first to conduct peripheral blood endothelial progenitor cell therapy for arteriosclerosis obliterans, and demonstrated its effectiveness (published in Lancet). These research achievements attracted great interest both in Japan and internationally, leading to awards from the Japanese Circulation Society and the Japan Society of Gene Therapy, as well as the Science Technology Award from the Minster of Education and Science.

Creation of Advanced Nanomedicine from Integration of the Unique Advanced Technologies (Medical Engineering and Nanotechnology) of Kyushu University

We have succeeded to create the innovative nanomedicine based on the integration of advanced technologies, and are working toward its clinical application. Press release of this achievement attracted great interest from the industrial sector. At present, partnership has been formed with medical equipment enterprises for projects toward practical application. Through this industry-university collaboration, we have established the foundation for the development of global standard treatment device (completely bioabsorbable nanotechnology-based drug delivery system [DDS] stent) and other innovative nanotherapies (including molecule-targeted therapy and therapeutic angiogenesis using nanoparticle DDS for arteriosclerotic disease, and nanotherapy for intractable lung diseases using inhaled nanotechnology-based DDS), which will realize minimally invasive therapies. Since our top priority goal is to apply the laboratory results to clinical treatment, translational research (from bench to bedside) in collaboration with the Department of Intellectual Property and the Highly Advanced Medical Center is in progress.

 

Synopsis of Research Achievements

基礎研究成果の臨床応用

Japan is facing an unprecedented aged population. Arteriosclerotic diseases (including myocardial infarction, angina pectoris, stroke, and arteriosclerosis obliterans of peripheral arteries) that are associated with lifestyle and aging continue to increase, and constitute the main cause of death and bed confinement. In our country which is heading toward an ultra-aging society, further increase of arteriosclerotic diseases will aggravate the already soaring medical expenditure to an extent that the society can longer support. To overcome this situation, “the health frontier strategy” with goals to prolong the healthy lifespan and promote health and security for the people needs to be undertaken at a national level. In this context, our research unit has set the objectives of “creation of molecule-targeted therapy based on the knowledge of molecular pathogenesis of arteriosclerotic diseases, and its clinical application (translational research)”. Based on the findings acquired from “basic research with clinical orientation”, we aim to research and develop novel diagnostic and therapeutic methods of global standards (“research to generate knowledge”). During this process, we pay special attention to “education to pass on knowledge” through training of our postgraduate students. By practical application of this “global standard”, “invented in Japan”, revolutionary next-generation medicine, we can expect to make “contribution to the society by applying the knowledge”.

To achieve these objectives, first of all we must gain a thorough knowledge of the molecular mechanisms of vascular diseases. For example, we hypothesized that “inflammation” plays a central role in the molecular pathogenesis of arteriosclerotic diseases, and conducted many studies to test this hypothesis (for details, see “Main Research Themes and Relevant Publications”)

As a result, we identified monocyte chemoattractant protein-1 (MCP-1), a monocyte/macrophage chemokine as the key molecule. Specifically, we demonstrated that inhibiting the function of MCP-1 (anti-MCP-1 gene therapy) or inhibiting MCP-1 expression (such as NF-κB inhibition, and vascular protection by ARB, statin, calcium antagonist, etc.) is able to control inflammation, resulting in the prevention of arteriosclerotic disease (restenosis or plaque instability) and hypertensive remodeling. 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. Specifically we found that (1) MCP-1 receptors exist 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.

We have already proceeded with the development of molecule-targeted therapies for vascular diseases based on the molecular pathogenesis identified in the above studies, and also clinical application of the therapies (translation research). For example, to develop clinical application of anti-inflammatory therapy based on MCP-1 inhibition (administration of 7ND gene or protein, administration of NF-kB decoy), it is essential to consider the needs of the present medical care system, the needs of the patients, and the needs of the market. The introduction of a drug delivery system is necessary to ensure “more effective” and “safer” medical treatment. The main ongoing research themes are listed below. For a synopsis of research and publications, please see “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
    ・Research and development of revolutionary medical devices (such as development of unique nanoparticle coating technology, invention of bioabsorbable polymer, development of bioabsorbable Mg stent, invention of nanoparticle coating stent, and production of nanotechnology-based DDS catheter).
    ・Creation of nanomedicine by the development of inhaled nanotechnology-based DDS (abbreviated as nano-DDS hereafter)
    ・Prevention of arteriosclerotic plaque rupture using selective monocyte/macrophage nano-DDS
    ・Minimally invasive angiogenesis therapy by selective vascular endothelial nano-DDS

Profile of Research Achievement

Until May 2007:
Original articles in English: 239
(N Engl J Med, The Lancet, J Clin Invest, Faseb J, Circulation, Circulation Res, etc.)
Total impact factor: 1567.942, mean impact factor: 7.396/article
Number of articles with impact factor 5 or above: 139, number with impact factor 10 or above: 60
Total number cited: 7,215
Mean number of citations: 35/article, number of articles with over 100 citations: 14, number with over 200 citations: 5

▲Page Top