血管病への分子生物学的アプローチ

Abstract

We analyzed the molecular basis of the pathogenesis of vascular disease.Firstly, we cloned three types of smooth muscle myosin heavy chain genes, SM1, SM2 and SMemb from rabbit cDNA library. Their expression during vascular development is differentially regulated at RNA levels. SM1 is constitutively expressed and SM2 appears after birth. Contrarily, SMemb is predominantly expressed in embryonic and perinatal stage. Interestingly, SMemb was reexpressed in proliferating smooth muscle cells of arteriosclerotic neointimas. These results suggest that smooth muscle proliferation is coupled to the expression of SMemb and that dedifferentiation of smooth muscles toward the embryonic phenotype is involved in the mechanisms underlying atherosclerosis.Secondly, we have also cloned macrophage scavenger receptor genes and determined their primary structures. The macrophage scavenger receptors showed unusual ligandbinding properties indicating higher binding affinity to modified LDL, such as oxidized and acetylated LDL rather than to LDL. These scavenger receptors were expressed in foam cells of the atherosclerotic neointima. An understanding of the structure and function of this family of receptors will provide us new insights into the mechanism of the development of atherosclerosis.Finally, we investigated cell-mediated autoimmunity in Takayasu's disease. We found that the dominant populations of the infiltrating cells in the arterial tissues obtained from patients with Takayasu's disease were large granular lymphocytes which contained a lot of perform. Our results suggested that cell-mediated cytotoxicity plays an important role in the development of arterial tissue damage involved in Takayasu's disease.