2003 Fiscal Year Final Research Report Summary
Molecular mechanisms of smooth muscle proliferation after arterial injury and prevention using gene therapies
| Project/Area Number |
14570644
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SUZUKI Jun-ichi Tokyo Medical and Dental University, Cardiovascular Medicine, Junior Lecturer, 医学部附属病院, 助手 (90313858)
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| Co-Investigator(Kenkyū-buntansha) |
AMANO Jun Shinshu University, Department of Surgery, Professor, 医学部外科学, 教授 (20138283)
ISOBE Mitsuaki Tokyo Medical and Dental University, Cardiovascular Medicine, Professor, 大学院・医歯学総合研究科, 教授 (80176263)
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| Project Period (FY) |
2002 – 2003
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| Keywords | inflammation / gene therapy / nuclear factor-kappa B / smooth muscle / coronary intervention / restenosis |
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| Research Abstract |
Background. The major disadvantage of the use of percutaneous coronary intervention (PCI) is the frequent occurrence of restenosis after an initially successful procedure; inflammation is a central event in this progression. Methods and Results. To evaluate the effectiveness of blocking inflammation to prevent neointimal formation, we made several murine and rat arterial remodeling models. We showed that anti-VCAM-1 antibody prevented arterial neointimal formation after arterial injury in a murine model. TNF receptor deficiency in donor organs suppressed coronary arterial neointimal formation in a murine heart transplant model. Anti-ICOS antibody suppressed inflammation in a myocarditis model or a transplantation model. An anti-selectin compound also showed suppressed ischemia reperfusion injury in rats. We performed several gene therapies to prevent arterial remodeling. Antisense Egr-1 or anti-MMP-2 ribozyme transfection prevented neointimal formation in murine cardiac transplantation models. Based on these results, we performed clinical trials to prevent restenosis after PCI. The initial case was suffering from effort angina with stenosis in the proximal and middle portions of the right coronary artery. The patient received two stents; we delivered the NF-kB decoy at the distal site and no decoy at the proximal site. Six months after the PCI, the NF-kB decoy suppressed restenosis compared to no decoy transfection. Condusion. Inflammation plays a pivotal role in arterial remodeling. These results suggest the clinical usefulness of gene transfection after PCI.
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