Smooth muscle cells, cholesterol

Dysfunction of the endothelium allows lipoproteins, predominantly low-density lipoprotein (LDL) cholesterol, and inflammatory cells, namely monocytes and T lymphocytes, to migrate from the plasma to the sub-endothelial space. Monocyte-derived macrophages ingest lipoproteins to form foam cells. Macrophages also secrete growth factors that promote smooth muscle cell migration from the media to the intima. A fatty streak consists of lipid-laden macrophages and smooth muscle cells and is the earliest type of atherosclerotic lesion. 

Cardiovascular heart diseases (CHD) are considered as the clinical expression of advanced atherosclerosis. One of the initial steps in atherogenesis is the oxidative modification of LDL and the uptake of the modified lipoprotein particles by macrophages, which in turn become lipid laden cholesterol-rich cells, so-called foam cells [159]. An accumulation of foam cells in the arterial wall is the first visible sign of atherosclerosis and is termed fatty streak, the precursor to the development of the occlusive plaque [160]. It is well known that oxidation of LDL can be initiated in vitro by incubating isolated LDL particles with cells (macrophages, lymphocytes, smooth muscle cells, or endothelial cells), metal ions (copper or iron), enzymes, oxygen radicals, or UV-light. However less is known about the mechanisms by which... 

Our most common lethal disease is atherosclerosis, which causes constriction and blockage of arteries of the heart, brain, and other organs. In the United States, Europe, and Japan half of all deaths can be attributed to this ailment.a,b There seems to be a variety of causes. However, there is agreement that the disease begins with injury to the endothelial cells that form the inner lining of the arteries.3/C/d This is followed by the aggregation of blood platelets at the sites of injury and infiltration of smooth muscle cells, which may be attracted by 12-hydrox-yeicosotetraenoic acid and other chemoattractants formed by activated platelets.c "Foam cells" laden with cholesterol and other lipids appear, and the lesions enlarge to become the characteristic plaques (atheromas). 

Cox, D.C., K. Comai, and A.L. Goldstein. 1988. Effects of cholesterol and 25-hydroxycholesterol on smooth muscle cell and endothelial cell growth. Lipids 23 85. 

Yin, J., Chaufour, X., McLachlan, C., McGuire, M., White, G., King, N., and Hambly, B., 2000, Apoptosis of vascular smooth muscle cells induced by cholesterol and its oxides in vitro and in vivo, Atherosclerosis 148 365-374. 

The hamster is susceptible to atherosclerosis. Nistor et al. (1987) fed male hamsters a hyperlipidemic diet consisting of standard chow supplemented with 3 % cholesterol and 15 % commercial butter for 12 months. Serum total cholesterol doubled after 3 weeks and attained a 17-fold value after 10 months. Up to 6 months, smooth muscle cells in the intima and media of the aorta as well as endothelial cells began to load with lipids. After 10 months the affected zones looked like human atherosclerotic plaque with huge cholesterol crystal deposits, calcium deposits and necrosis. 

LDL is oxidatively modified when incubated in vitro with three major cellular constituents of the vascular wall endothelial cells [35], vascular smooth muscle cells [35] and macrophages [35-37], The uptake of oxidised LDL occurs via the scavenger-receptor pathway, and expression of scavenger receptors has been demonstrated on macrophages, endothelial cells [38], fibroblasts [39] and smooth muscle cells [39]. Unlike the LDL receptor, expression of the scavenger receptor is not down-regulated by an increase in intracellular cholesterol [40]. Therefore, uptake of Ox-LDL contributes to the accumulation of cholesteryl esters in foam cells of atherosclerotic lesions [40]. Now, the question is Does oxidation of LDL-lipids influence the development of atherosclerosis ... 

Figure 9.1 The progression of CRD as a continuum, affected by a host of risk factors (with cigarette smoking, high cholesterol, and hypertension as the three major risk factors) and protective factors including resveratrol. The scheme also shows that multiple cell types, such as endothelial and smooth muscle cells, and platelets and macrophages, are involved in the pathogenesis of CRD.

As a result of hypercholesterolemia, an intracellular accumulation of cholesteryl esters occurs, which is associated with the initiating events of atherogenesis, in particular, foam cell generation, which involves the intracellular accumulation of large amounts of cholesterol within macrophages and smooth muscle cells of aorta (76). 

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. 

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