Muscle atherosclerotic process

The chemotaxis of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical for the chronic inflammatory and fibroproliferative response in atherosclerosis (Ml). Chemokine-mediated attraction of leukocytes to tissues has been shown in atherosclerotic lesions (G8). Studies using knockout and transgenic murine models indicated that chemokine receptor/ligand interactions are crucial in the development of atherosclerosis (P6). Moreover, chemokines may also interfere with smooth muscle cell migration and growth, and platelet activation and other well-defined features of the atherosclerotic process (A2). 

Both the HDL-dependent and the HDL-independent pathway protect the macrophage and maybe other cholesterol-loaded cells from overaccumulation of cholesterol and foam cell formation. Cholesterol accumulation and inflammatory activation trigger the macrophage to synthesize and secrete a large variety of secretory products including enzymes, proteins, and growth factors for fibroblasts, endothelial cells, and smooth muscle cells which enhance the atherosclerotic process. 

The atherosclerotic lesions develop in a complex, chronic process. The first detectable lesion is the so-called fatty streak, an aggregation of lipid-laden macrophage foam cells. The next stage of development is the formation of plaques consisting of a core of lipid and necrotic cell debris covered by a layer of connective tissue and smooth muscle cells. These plaques hinder arterial blood flow and may precipitate clinical events by plaque rupture and thrombus formation. Platelets from the thrombi, activated macrophages, and smooth muscle cells release growth factors and cytokines resulting in an inflammatory-fibroproliferative response that leads to the advanced lesions of atherosclerosis. 

Oxidative stress is now widely believed to be the major mechanism of athero-genesis. Interestingly, it was demonstrated 47 years ago that atheromatous plaques contain abundant lipoperoxides and other lipid peroxidation products (G9). More recently, our understanding of this process was advanced when evidence was provided for significant free radical activity and the lipid oxidative modification hypothesis was presented (P10). A subsequent study provided further evidence that oxidatively modified low-density lipoproteins (LDL) play a major role in the formation of the fatty streak, the earliest visible atherosclerotic lesion, and the subsequent production of the atheroscelrotic plaque (S27). The proposed sequence, which involves arterial endothelial and smooth muscle cells, as well as mono-cytes/macrophages, is as follows (Ql, S25). 

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

Coronary arteries frequently narrow because of atherosclerotic plaques. Coronary occlusions may occur and regions of heart muscle may be deprived of blood and, therefore, of oxygen for prolonged periods of time. Lack of oxygen causes inhibition of the processes of electron transport... 

Cardiovascular Effects. PAHs are contained in cigarette smoke, and smoking is a well-established risk factor in the development of atherosclerosis. Arterial smooth muscle cell proliferation, collagen synthesis, lipid accumulation, and cellular necrosis are all involved in the pathogenesis of the atherosclerotic plaque. In v//ro studies conducted using bovine, rabbit, and human smooth muscle cells from arteries demonstrated that benzopyrene affects some of the aforementioned processes. 

However, in addition to this receptor-mediated LDL uptake, cells can also internalize LDL by a bulk-phase pinocytosis which does not require specific cell-surface binding. In this situation LDL is taken up at a rate proportional to the environmental concentration. At low extracellular LDL concentrations the bulk process is insignificant when compared to the receptor mediated uptake. However at elevated LDL concentrations although receptor-mediated uptake becomes rapidly saturated, bulk phase pinocytosis increases in rate proportionately to the overall LDL concentration. The smooth muscle cells in the normal atherosclerotic lesion accumulate lipid by this receptor-independent process which is not subject to feedback control. In addition to this a relative deficiency of lysosomal cholesteryl ester hydrolase activity in the presence of overwhelming concentrations of substrate may also contribute to the aggrevated situation. 

---