MOLECULAR MEDICINE AND GENE-THERAPY - THE EXAMPLE OF ARTERIOSCLEROSISAND RESTENOSIS

Atherosclerosis and its consequences account for most morbidity and mo rtality in Western countries. Atherosclerosis develops over a period o f decades and has a complex pathogenesis. It is a disease of the intim a and primarily involves four cell types, i.e. endothelial and vascula r smooth muscle cells, monocytes and platelets. In recent years, eluci dation of the cellular and molecular mechanisms of these cells, and th eir alterations by cardiovascular risk factors and in atherosclerosis, has markedly expanded knowledge of this disease. In particular, it be came clear that endothelial cells play a crucial role in the regulatio n of platelet function and coagulation, as well as vascular zone and s tructure. Interestingly, endothelial dysfunction occurs early on in th e presence of cardiovascular risk factors such as hyperlipidemia, hype rtension and diabetes. This could lead to adhesion of circulating plat elets and monocytes, increased accumulation of lipids in the subintima , increased contraction, migration and proliferation of vascular smoot h muscle cells. The fact that atherosclerosis develops only in some bu t not in other parts of the circulation, however, has rarely been cons idered. With the development of molecular biology it has now become po ssible to clone differentially expressed genes in vessels with or with out atherosclerosis; this in turn makes it possible to characterize be tter the molecular and cellular mechanisms of the disease. The search for such candidate genes could form the basis for future genetic inter ventions. This therapeutic approach is likely to assume clinical impor tance, particularly in monogenetic diseases (i.e. familial hypercholes teremia), while its use in complex polygenetic diseases such as athero sclerosis is more difficult. Restenosis, however, may be accessible to gene therapy earlier on as it is accessible to local gene transfectio n.