2000 Fiscal Year Final Research Report Summary
Pathophysiological analysis and gene therapy of thoracic and abdominal aortic aneurysm
| Project/Area Number |
10470162
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 (1999-2000)
Shinshu University (1998) |
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Principal Investigator |
ISOBE Mitsuaki Tokyo Medical and Dental University, Department of Cardiovascular medicine, Associate Professor, 医学部・附属病院, 助教授 (80176263)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Aortic aneurysm / myosin heavy chain / extracellular matrix / atherosclerosis / apoptosiss / cardiac transplantation / remodeling / gene therapy |
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| Research Abstract |
1. The pathogenesis of aortic abdominal aneurysm (AAA) and thoracic aneurysm formation remains uncertain. Enzymes that weaken the extracellular matrix appear crucial in plaque rupture and smooth muscle cell (SMC) migration and may contribute to aneurysm formation. Matrix metalloproteinases (MMPs) degrade components of the vascular extracellular matrix and are regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). SMCs may also participate in matrix remodeling through localized production of various proteinases and their inhibitors. To determine whether phenotypic modulation and proteolytic activity in vascular SMCs contributes to arterial medial degeneration, we examined Smisoforms, MMPs and TIMPs in SMCs in 17 patients with AAA who underwent surgical treatment. We clarified that balance shifted to SMemb predominance in the diseased aortas. SMemb expression is increased in aneurysm with MMP enhancement, and a significant imbalance of SMemb/SM2 and MMP/TIMP was revealed in
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rapid progression of AAA.
2. The goal of the second project was to explore the possibility that gene therapy of MMPs is effective in stabilizing aortic aneurysm. We tested an efficacy and safety of gene transfer to the vessel wall by HVJ-liposome method. We used ectopically transplaned murine heart and its coronary arteries as an animal model, because of the similarity in pathogenesis of vascular lesions between chronic rejection and AAA.FITC-labeled ODN was infused into coronary arteries of explanted heart before transplantation on ice for ten minutes by HVJ-liposome method. FITC was detected on coronary arteries of transplanted heart as long as 2 weeks. Antisense bcl-x and PCNA ODN were effective in inhibition of neointimal formation in this animal model. We also used ectopic heart transplatation in monkeys to ensure the safety of this technology. E2F decoy DNA fragment was transferred to explanted heart just as the mouse model. The decoy was expressed on donor heart and recipients appeared healthy. We conclude that this technique is useful for delivery of ODN to arterial wall.
3. Next step would include generation of antisense MMPs ODN or MMP ribozyme and development of an animal model of AAA.The effect of MMP inhibition by gene therapy could by evaluated using these experimental systems. Less
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[Publications] Tsukioka K,Suzuki J,Kawauchi M,Wada Y,Zhang T,Nishio A,Koide N,Endoh M,Takayama K,Takamoto S,Isobe M,Amano J: "Expression of membrane-type 1 matrix metalloproteinase in coronaryvessels of allotransplanted primate hearts."J Heart Lung Transplant. 19. 1193-1198 (2000)
Description
「研究成果報告書概要(和文)」より
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[Publications] Kamijima T,^*Isobe M,Suzuki J,Izawa A,Kumazaki S,Fukui D,Arai M,Urayama H,Nishimaki K,Sekiguchi M,Kawasaki S: "Enhanced Embryonic Nonmuscle Myosin Heavy Chain Isoform And Matrix Metalloproteinase Expression in Aortic Abdominal Aneurysm With Rapid Progression"Cardiovasc Pathol. 8. 291-295 (1999)
Description
「研究成果報告書概要(和文)」より
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[Publications] Kawauchi M,Suzuki J,Morishita R,Wada Y,Izawa A,Tomita N,Amano J,Kaneda Y,Ogihara T,Takamoto S,Isobe M: "Gene therapy for attenuating cardiac allograft arteriopathy using exvivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhumanprimates"Circ Res. 87. 1063-1068 (2000)
Description
「研究成果報告書概要(和文)」より
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[Publications] Kamijima T, ^*Isobe M, Suzuki J, Izawa A, Kumazaki S, Fukui D, Arai M, Urayama H, Nishimaki K, Sekiguchi M, Kawasaki S: "Enhanced Embryonic Nonmuscle Myosin Heavy Chain Isoform And Matrix Metalloproteinase Expression in Aortic Abdominal Aneurysm With Rapid Progression."Cardiovasc Pathol. 8. 291-295 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kawauchi M, Suzuki J, Morishita R, Wada Y, Izawa A, Tomita N, Amano J, Kaneda Y, Ogihara T, Takamoto S, Isobe M: "Gene therapy for attenuating cardiac allograft arteriopathy using ex vivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhuman primates."Circ Res. 87. 1063-1068 (2000)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Tsukioka K, Suzuki J, Kawauchi M, Wada Y, Zhang T, Nishio A, Koide N, Endoh M, Takayama K, Takamoto S, Isobe M, Amano J: "Expression of membrane-type 1 matrix metalloproteinase in coronary vessels of allotransplantated primate hearts."J Heart Lung Transplant. 19. 1193-1198 (2000)
Description
「研究成果報告書概要(欧文)」より
