**3. Anti-Atherogenic and Anti-Atherosclerotic Drugs**

Taken together, our data allow us to identify possible targets for anti-atherosclerotic thera‐ py. The first target is atherogenic modification (desialylation) of LDL particle in blood. Pre‐ vention of LDL modification may be an approach to anti-atherosclerosis therapy. The second approach may be selective removal of modified LDLs from blood (target 2). The third one may be based on prevention of modified LDL accumulation in arterial cells (target 3). Also one more approach is removal of excess lipids from foam cells (target 4). Figure 1 schematically represents these four approaches. We have used all of these approaches and now we believe that the most suitable approach is the third one, namely, the prevention of modified LDL accumulation in arterial cells. Bellow we describe the application of this ap‐ proach for the development of anti-atherosclerotic therapy.


rosclerotic drug therapy.

lines of subendothelial cells [32].

the results obtained are relevant to human atherosclerosis.

The identification of anti-atherosclerotic or/and anti-atherogenic activities of a drug is asso‐ ciated with considerable difficulties. There are no simple and rapid techniques to estimate the anti-atherogenic/anti-atherosclerotic effect of a drug in an animal model or in clinical tri‐ als. That is why we employ a culture of human atherosclerotic vascular cells in the screening of potential drugs, investigation of their mechanisms of action and optimization of anti-athe‐

Use of Natural Products for Direct Anti-Atherosclerotic Therapy

http://dx.doi.org/10.5772/52967

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We use human aortic cells to examine the effects of various agents on atherosclerosis-related features of cultured cells. Cells are isolated from the subendothelial part of the human aortic intima, i.e. from the part of aorta which is localized between the endothelial lining and the media [32]. The intima of adult human aorta is a well-defined structure. The thickness of a normal intima varies from 50 to 120 µm [32]. Sometimes a thickened intima is called a dif‐ fuse intimal thickening [32]. This term underlines its essential difference from a very thin in‐ tima of animal and adolescent aorta. Unaffected intima of adult human aorta contains 10-12

Using collagenase and elastase, cells are isolated from the subendothelial layer of the intima of both normal and atherosclerotic parts of the aorta [33-36]. This approach makes it possible to study a direct anti-atherosclerotic and anti-atherogenic action of a drug at the vascular cell level. An important advantage of this technique is that human material is used and thus,

By the well-established criteria, the cells cultured from the intima can be classified as the cells of smooth muscle origin. These cells are stained with antibodies to smooth muscle myosin [33-35]. For further identification of cultured cells we have used a monoclonal antibody HHF-35 which reacts specifically with muscle α-actin and can reveal smooth muscle cells [37]. Accord‐ ing to our calculations, primary culture of subendothelial cells contains about 90% of smooth muscle cells interacting with HHF-35. In addition, cells cultured from subendothelial part of uninvolved (healthy) intima have the ultrastructural features characteristic of smooth mus‐ cle cells, namely: the basal membrane and filament bundles with dense bodies [33-36]. The culture on which our experiments are performed is represented by mixed population of typical

Cells of the subendothelial intima isolated from atherosclerotic lesions retain in primary cul‐ ture all major characteristics of atherosclerotic cells. Cells cultures from fatty streak and fatty infiltration zones have an enhanced proliferative activity [38]. These cells have a higher pro‐

Many cells cultured from atherosclerotic lesions are so called foam cell containing numerous inclusions filling the whole of the cytoplasm, these inclusions are lipid droplets [34]. The

liferative activity as compared with the cells cultured from unaffected intima [38,39].

and modified smooth muscle cells revealed in the human aorta earlier [32].

**4. Cell Model**

Agents capable of preventing atherogenesis are anti-atherogenic drugs, agents promoting the regression of atherosclerotic manifestations are anti-atherosclerotic drugs. Prevention of intracellular lipid accumulation accompanied by the stimulation of arterial cell proliferation and massive extracellular matrix production may be regarded as anti-atherogenic (preven‐ tive). In terms of arterial cells, any drug effect which does not prevent directly the conver‐ sion of the normal cell into an atherosclerotic one (foam cell) should be regarded as an indirect anti-atherogenic action. Only that drug which exhibits its preventive activity at the arterial level is a direct anti-atherogenic drug. At the arterial cell level, a drug with a direct anti-atherosclerotic action should induce the regression of the major cellular manifestations of atherosclerosis, i.e. reduce the intracellular lipid content, suppress cell proliferation and inhibit the extracellular matrix production.

**Figure 1.** Targets of anti-atherosclerotic and anti-atherogenic drug actions

Solid circles, multiple modified LDL; open circles, native LDL

(see explanation in the text).

Thus, the drugs that affect atherosclerosis can be divided into 3 groups:


