Pathophysiological analysis and gene therapy of thoracic and abdominal aortic aneurysm

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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 … More 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