Development of new diagnostic and therapeutic methods and animal models of cardiovascular diseases using smooth muscle myosin heavy chain isoforms.

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We previously demonstrated that rabbit and rat smooth muscles contain at least three types of MHCs ; SM1 (204kDa), SM2 (200kDa) and SMemb (200kDa). SM1 and SM2 are two smooth muscle specific MHC isoforms arising from a single gene, and SMemb is a third type of MHC isoform abundantly expressed in embryonic aortas. The expression of three MHC isoforms is developmentallyregulated.The presence of developmentallyregulated MHC isoforms in vascular smooth muscles provides importantmoleculartools to investigate the molecularmechanism underlying vascular diseases. We first developed an immunoassay for smooth muscle myosin heavy chain isoform (SM1) which could be released into circulation following vascular injury. This assay is sensitive and specific enough to detect circulating SM1 after acute aortic dissection in clincal cases. The sensitivity and specificity of our SM1 assay for diagnosis of aortic dissection were 87% and 97%, respectively.In order to understand the molecular mechanisms underlying smooth muscle de-differentiation and proliferation occurring in atherosclerosis and restenosis, we characterized the promoter region of the SMemb gene. In this study, we identified a cis element and a transcription factor, BTEB-2, which coordinately regulate the SMemb gene.We furthemore developed a transgenic mouse in which a single gene was coincidentally knocked out, which resulted in accelerated aging process including atheosclerois, pulmonary emphysema and reduced insulin secretion.