Development of Direct Anti-Atherosclerosis Drugs on the Basis of Natural Products
- Pp. 92-133 (42)Alexander N. Orekhov, Alexandra A. Melnichenko and Yuri V. Bobryshev
Based on the existing knowledge of the cellular mechanisms that govern in atherosclerosis development, several sites of action for the agents capable of preventing atherogenesis or promoting the regression of atherosclerotic manifestations can be suggested. The main manifestation of plaque development relates to the formation of foam cells in the arterial intima. It is reasonable to consider that any drug which would not prevent directly the transformation of normal intimal cell into an “atherosclerotic” one (namely, foam cell) should be regarded as an indirect anti-atherogenic action drug. Only that drug which would exhibit its preventive activity focally, at the arterial wall level, is a direct anti-atherogenic drug. At the arterial cell level, a drug with a direct anti-atherosclerotic action should be capable to induce the diminishing of the major cellular manifestations of atherosclerosis, i.e. reduce the intracellular lipid content, suppress cell proliferation or inhibit the extracellular matrix production. </p><p> In our current work we examine the effects of various agents (drugs) on atherosclerosisrelated features of cultured arterial human cells. In these experiments, cells are isolated from the subendothelial portion of the human aortic intima, i.e. from the part of the aorta which is located between the endothelial lining and the tunica media. The intima of the adult human aorta has a distinctive structure allowing us the identification of its different layers. Using collagenase and elastase, cells are isolated from the subendothelial layer of the intima of both normal and atherosclerotic parts of the aorta. This approach makes it possible to study a direct anti-atherosclerotic action of various drugs at the vascular cell level. An important advantage of this approach is that human material is used and thus, the examinations which we carry out are relevant to human atherosclerosis. </p><p> Cells of the subendothelial intima isolated from atherosclerotic lesions have been proved to retain all major characteristics of atherosclerotic cells in primary cell culture. Cells cultures obtained from fatty streaks and fatty infiltration zones have an enhanced proliferative activity. A large proportion of cells cultured from atherosclerotic lesions are foam cells containing numerous inclusions that fill the most space of the cytoplasm; these inclusions represent lipid droplets. The excess lipids in foam cells are cholesterol and cholesteryl esters. It should be noted that the content and composition of lipids in cultured cells remain unchanged within the first 10-12 days of the cultivation and retain the properties of the freshly isolated cells. Cultivated cells that obtained from the intima are capable of synthesizing collagen, proteoglycans and other components of the extracellular matrix. Thus, cells isolated from an atherosclerotic lesion of the human aorta retain in culture all main properties, typical to atherosclerotic lesion cells. They exhibit an enhanced proliferative activity, contain excess cholesterol in the form of intracellular inclusions and synthesize the extracellular matrix. This allows one to regard primary culture of atherosclerotic cells as a convenient model for the investigation of effects of various agents on atherosclerotic manifestations. Therefore, the in vitro investigations are carried out directly on exactly the same cells which would “face” with a therapeutic action in vivo. </p><p> Using such cell model, we have examined the effects of different drugs and chemicals. Many substances have been already tested. Some of the tested drugs elicited antiatherosclerotic effects in cell culture, others have been proved to be ineffective against cellular atherosclerotic manifestations; some tested substances have been found to.... stimulate the development of atherosclerotic features.