PKC Inhibitors is associated with endothelial dysfunction

Atherosclerosis is initiated by the deposition, retention and oxidative modification of apolipoprotein (apo)B-containing lipoproteins, notably low-density lipoprotein cholesterol (LDL-C) in the vessel wall. PKC Inhibitors is associated with endothelial dysfunction and recruitment of monocytes that take up oxidised LDL to become macrophage-derived foam cells, collectively apparent macroscopically as "fatty streaks". Subsequent proliferation of vascular smooth muscle cells and secretion of extracellular matrix contribute fibrous elements, whereas accumulation of lipid and inflammatory cell debris forms the necrotic lipid core of the mature atherosclerotic plaque. Both the size and composition of plaques determine the clinical course. The so-called "vulnerable plaque" typically has a large lipid core, thin fibrous cap and inflammatory cell Vismodegib infiltrate.

Acute atherothrombotic complications arise when rupture or erosion of the cap exposes thrombogenic plaque components. Animal models have contributed considerably to our understanding of atherogenesis and the influence of lipids and lipid-modifying treatments. In early work, Pazopanib feeding a high-fat diet to monkeys caused hypercholesterolaemia and accelerated the development of atherosclerosis. Subsequent resumption of a normal diet induced moderate disease regression.4 More recently, mouse models that permit precise genetic manipulation have come to predominate. Normal mice have total plasma cholesterol of about 2.5 mmol/l (100 mg/ dl), of which the majority is high-density lipoprotein cholesterol (HDL-C), and are resistant to atherosclerosis.
However, mice lacking apoE, which is involved in the clearance of circulating lipoproteins, are markedly hypercholesterolaemic and develop atherosclerotic lesions that become complex and share some features in common with those found in humans. Correction of hypercholesterolaemia and subsequent regression of early foam cell lesions has been attained by somatic apoE gene transfer using an adenovirus vector.5 However, short-lived expression of apoE is a limitation that precludes the study of regression of advanced, more clinically relevant, lesions. Instead, such lesions have been studied by the transplantation of an atherosclerotic aortic segment from apoE-deficient mice into syngeneic wild-type mice with a non-atherogenic lipid profile.
6 In this model, reducing cholesterol by 90% produced substantial reductions in the size and foam cell content of Bortezomib atherosclerotic lesions (fig 1). The first experimental evidence of a protective effect of HDL-C elevation was obtained by Badimon et al.7 Serial injections of purified HDL into cholesterol-fed rabbits resulted in diminished atherosclerosis after 90 days, relative to controls. More recently, the ability to attain sustained HDLC increases in mice by transgenic expression of its principal apolipoprotein, apoA-I, has enabled a series of experiments Gefitinib determining the effects of HDL-C increases on plaque size and composition,8 9 in addition to effects on remodelling advanced (American Heart Association classes III?CV) plaques.10The dynamic, reversible nature of atherosclerosis shown in these animal experiments raises the exciting possibility that, by using potent new treatments, clinically important plaque regression and remodelling may be attainable in humans. However, enthusiasm for these findings should be tempered with the caveat that discoveries in animal models do not always lead to effective clinical treatments??see later discussion of acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors.

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