Gene Therapy of Combined Nitric Oxide Synthases and Related Enzymes to Achieve Complete Regression of Advanced Atherosclerosis-Combined Regulation of Substrate of the Enzymes, Co-factors, Transcriptional Factors and Intracellular Enzymes-

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Background)We previously found the partial regression by in vivo gene transfer of eNOS in balloon injury + high-cholesterol diet induced atherosclerosis in rabbit. (JSPS Grant-in-Aid for Scientific Research (B) project number 09470166). However, the regression was not sufficient and the mechanism was not well known.Objectives)We investigated the possibility of the sufficient regression by combined gene transfer of eNOS, iNOS and related enzymes in atherosclerotic arteries.Methods)1) We investigated the possibility of the sufficient regression by combined gene transfer of eNOS, iNOS or eNOS+iNOS in advanced atherosclerotic arteries. 2)We produced adenovirus vector of ERα(estrogen receptor α). 3)We prepared the arteries from spontaneously developed diabetic rats and those from senile rats. We investigated the effect of gene transfer of eNOS, iNOS or eNOS+iNOS on their vascular function. 4)We elucidated the function of acylation and caveolae with the relation to eNOS in endothelial cells. … More 5)We elucidated the effect of promotion or inhibition of iNOS in vascular function. 6)We investigated the possibility of the sufficient regression by combined gene transfer of eNOS, iNOS or ERα in advanced atherosclerotic arteries.Results)1)In vivo gene transfer of eNOS, but not iNOS or eNOS+iNOS partially regressed the advanced atherosclerotic arteries. 2)We produced adenovirus vector of ERα and observed the increase of NO release its gene transfer on. 3)We prepared the arteries from spontaneously developed diabetic rats and those from senile rats. We eNOS gene transfer improved their vascular function. 4)Acylation of eNOS is critica for survival of endothelial cell. The morphology of caveolae changes with the relation of eNOS activity. 5)SiRNA of iNOS improved vascular function. 6)We achieved the partial but sufficient regression by combined gene transfer of eNOS plus ERα,but not iNOS in advanced atherosclerotic arteries.Conclusion)Combined gene transfer of eNOS plus ERα,but not eNOS plus iNOS or iNOS plus ERα made possible partial but sufficient regression in advanced atherosclerotic arteries. Combined gene transfer may become one tool to achieve regression of atherosclerosis. Less