THE POTENTIAL OF TRANSGENIC ANIMAL-MODELS IN CARDIOVASCULAR RESEARCH

By means of molecular biology and genetic research the influence of ge netic factors on a great variety of human diseases could be shown. In the field of cardiovascular research the genetic defects of a few mono genetic disorders, such as Marfan's syndrome and hypertrophic cardiomy opathy, have been characterized. In addition, candidate genes for poly genetic diseases, such as arterial hypertension and atherosclerosis, h ave been cloned. However, the identification of a candidate gene or it s mutation does not prove its influence on the phenotype or the final cause of a particular disease. Only a targeted manipulation of a defin ed candidate gene in a transgenic animal model helps to understand the role of the gene and its product in the whole organism. Transgenic ex periments can be divided into gene-addition and gene-deletion models. In a gene-addition experiment a fusiongene is microinjected into a fer tilized oocyte. The fusiongene itself consists at least of a regulator y element promoter and of a DNA sequence coding for the gene product ( protein) of intended overproduction. The choice of the right promoter is important for obtaining tissue-specific gene expression. The cardia c myosin light chain-2 promoter for example leads to a ventricle-speci fic gene expression in cardiomyocytes from early embryogenesis through adulthood. In a gene-deletion experiment on the other hand, the targe t gene is selectively knocked out by homologous recombination in embry onic stem (ES) cells. The selected ES-cells are then injected into bla stocysts. If the ES-cells are integrated into the germ line and transm itted to the progeny, a transgenic line is established. This review ar ticle describes planning and development of transgenic animals and dis cusses established transgenic animal model systems with regard to card iovascular physiology. In addition, animal models which may provide a basis for future gene therapy will be introduced.