The underlying cause of coronary heart disease is atherosclerosis, which from a clinical view leads to the formation of plaque, degeneration of vessel intima, thro-mobosis, and ultimately vessel occlusion and ischemia. An interesting aspect of atherosclerosis is that it occurs more frequently at certain locations than others in the vasculature, albeit throughout the body. Atherosclerosis is commonly located at bifurcations and areas of vessel stress. These areas often have a low oscillating shear stress. Presumably, this stress facilitates the accumulation of lipid and initiation of atherosclerosis.42 In recent years, oxidation and inflammation have been viewed as primary mechanisms in the initiation and progression of atherosclerosis. Oxidative damage and inflammation have been linked with the risk of coronary heart disease in several instances.43,44 Together, these observations suggest that factors other than hypercholesterolemia alone are important in the generation of atherosclerosis and vessel damage. The "oxidation hypothesis" was developed and states that non-specific oxidative damage induces the formation of oxidized LDL and the initial stages of atherosclerosis.45 This hypothesis also is consistent with the idea of a "response-to-injury" model,46 wherein inflammation is a response to an initial injury of the vasculature; in this case, possibly due to oxidative damage.
Oxidative damage and inflammation may be tightly linked in the developmental atherosclerosis and subsequently cardiovascular disease. Oxidative stress can be elevated as a result of lifestyle factors and subject characteristics, such as an elevated BMI.43 It may initiate vascular damage that precedes inflammation. Inflammation is a response to the oxidative vascular damage, which also precipitates further oxidative damage. Oxidative damage, in turn, leads to the generation of oxidized lipids, which are bioactive and induce inflammation. Both oxidative damage and inflammation have been associated with several stages in the pathogenesis of atherosclerosis. While the exact order of events is not well established, we could envision a sequence of reactions involving an increase in oxidative stress which leads to vessel damage, accompanied by the production of bioactive lipids and consequently an inflammatory response, which generates further oxidative damage and atherosclerosis.
Pioneering research in the 1980s found that cellular uptake of cholesterol in the form of LDL particles was a very tightly controlled process. It did not allow accumulation of excess unesterified (free) cholesterol by cells; several control mechanisms maintained cellular unesterified cholesterol levels at a constant level.47 This observation was inconsistent with observation of foam cell formation, which was characterized by excessive uptakes of LDL particles and cholesterol by macrophages and smooth muscle cells. Then a fundamental set of experiments found that modifications of LDL led to an uncontrolled uptake of LDL particles by macro-phages.48 Modifications, which induced LDL uptake, included acetylation and oxidation as well as several modifications generally considered unphysiological. Modification allowed for identification of the LDL particle by a scavenger receptor (CD36).49 This receptor was not controlled by cellular cholesterol levels and provided for the accumulation of cellular cholesterol and formation of foam cells, and subsequently the squeale leading to the formation of advanced atherosclerotic plaque. These studies induced a massive expansion of vascular biology research and identification of the mechanisms involved in the development of atherosclerosis. Oxidative stress and damage produced vascular damage in the form of oxidized LDL particles.50 The damaged particles induced a "response-to-injury", which was an inflammatory response. Thus, an interaction between lipids, oxidative stress, and inflammation may provide an environment for the development of atherosclerosis.
The pathogenesis of atherosclerosis can be divided into three stages consisting of fatty streak formation, development of advanced (fibrous) plaque, and thrombosis.51 In the initial stage, there may be an increase in vessel permeability and a movement of LDL particles into the subendothelial space of vessels. LDL becomes oxidized forming an oxidized particle and bioactive oxidized lipids; some of which induce an inflammatory response. These activities induce the expression of chemotactic factors (MCP-1, Fractalkine and Rantes) and adhesion molecules
(P-selectin, ICAM, VCAM-1, Cs-1, and fibronectin) by endothelial cells, which facilitate monocyte migration and uptake. Under these conditions, there is also an elevation in monocyte differentiation factors (M-CSF, IL-8, GM-CSF). Simultaneously, lymphocyte activity is enhanced by chemotactic factors. The macro phages and lymphocytes produce reactive oxygen species, which cause further oxidative damage and macrophage uptake of oxidized LDL via scavenger receptors (CD36, SRA-1, and LOX-1). Foam cell formation occurs and ultimately leads to the development of fatty streaks. This activity is facilitated by a decrease in the release of cholesterol from macrophages via ABCA-1 and ABCG-1. Together these activities may be regarded as an initial "response to injury."
The development of advanced plaque is a complex process, which involves several distinct activities and cell types. These include an increase in smooth muscle proliferation, which is induced by FGF-1, HBEGF, and PDGF, and the movement of smooth muscle cells into plaque. It is facilitated by the smooth muscle cell chemotactic factor, PDGF. Smooth muscle cells can participate in the uptake of oxidized LDL and matrix synthesis, which is stimulated by TGFbeta. Also, basement membranes around the plaque can be remodeled through the actions of metallopro-teinases. During this phase, there can be development of a necrotic core, which is formed from the death of foam cells through necrosis or apoptosis. Necrosis and apoptosis also cause the formation of oxidized bioactive lipids, some of which have thrombotic activities.
The final stage of atherosclerosis is the induction of thromobosis. This includes changes in the release or expression of prothromobotic molecules from endothelial cells, many of which are oxidized lipids, including tissue factor, plasminogen activator, and plasminogen activator inhibitor. It includes increased smooth muscle and macrophage expression of tissue factor and other prothromobotic molecules. Also, the weakening and possibly the rupture of the vessel wall through activities of met-alloproteinase's and their inhibitors. These activities promote the development of cardiac events.
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