MOLECULAR AND CELLULAR MECHANISM OF ATHER OSCLEROSIS AND RESTENOSIS -PERSPECTIVES OF GENE-THERAPY

Atherosclerosis and its consequences account for most of morbidity and mortality in Western countries. Atherosclerosis develops over a perio d of decades and has a complex pathogenesis. It is a disease of the in tima and primarily involves four cell types, i.e., endothelial and vas cular smooth muscle cells, monocytes and platelets. In recent years, k nowledge on the cellular and molecular mechanisms of these cells and t heir alterations by cardiovascular risk factors and in atherosclerosis has greatly expanded. In particular, it became clear that endothelial cells play a crucial role in the regulation of platelet function, coa gulation as well as vascular tone and structure. Interestingly, endoth elial dysfunction occurs early, particularly if cardiovascular risk fa ctors such as hyperlipidemia, hypertension and diabetes are present. T his could lead to adhesion of circulating platelets and monocytes and increased accumulation of lipids in the subintima as well as increased contraction, migration and proliferation of vascular smooth muscle ce lls. The fact that atherosclerosis develops only in certain, but not i n other parts of the circulation, however, has rarely been considered. With the development of molecular biology techniques it became possib le to clone differentially expressed genes in vessels with or without atherosclerosis; this in turn allows to better characterize the molecu lar and cellular mechanisms of the disease. The search for such candid ate genes could set the basis for future genetic interventions. This t herapeutic approach is likely to reach clinical importance particularl y in monogenetic diseases (i.e., familial hypercholesterinemia), while its use in complex polygenetic diseases such as atherosclerosis is mo re difficult. Restenosis, however, may be accessible to gene therapy e arlier on as it is amenable to local gene transfection.