How does atherosclerosis develop

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A comprehensive description of the sequence of events in atherogenesis is beyond the focus of this review, but has been well described in several review papers [4-7]. The hallmark feature of atherosclerosis is focal and chronic inflammation in the arterial wall. Inflammation constitutes the first response of innate immunity after a threat is detected, indicating that atherosclerosis is first and foremost an immune-based disease [4]. Virtually all major and minor cellular effectors of the immune system have been shown to be present and in most cases instrumental in the development of plaque [4, 8-11]. Briefly, development of atheromata begins when lipoproteins are retained within the arterial subendothelial matrix [12] (Fig. 1). Why serum lipoproteins become trapped in the arterial subendothelium remains unclear. The Framingham Heart Study and many others unequivocally established that risk of myocardial infarction or stroke increases linearly with serum low-density lipoprotein (LDL) cholesterol levels [13, 14]. Nevertheless, subendothelial lipoprotein retention is probably not a simple function of serum LDL levels for a number of reasons: (1) kinetic analyses suggest that trapping of lipoproteins is explained more by selective retention rather than increased delivery [15, 16]; (2) selective mutations of apoB100 that alter its ability to interact with proteoglycans in the extracellular matrix does not change transendothelial flux of lipoproteins, but plaque development is inhibited [12]; (3) the propensity of the extracellular matrix to retain lipoproteins has a strong genetic component [17]; (4) atherosclerosis occurs rarely in veins and many arteries, implying that lipoproteins are not retained there either, despite presumably similar subendothelial extracellular matrix composition; (5) atherosclerotic plaque tends to be focal, unevenly distributed and does not develop linearly with time; (6) patients with extensive atherosclerosis can present with normal serum cholesterol levels and lipoprotein profiles and atherosclerosis develops in some individuals with quite low serum cholesterol; (7) the established ability of HMG Co-A reductase therapy to stabilize plaques and slow the progress of atherosclerosis does not necessarily involve significant changes in lipoprotein profiles [18, 19]. Interestingly however, smooth muscle cells (SMCs) treated with statins secrete an extracellular matrix that resists lipoprotein retention [20]. Once trapped in the subendothelial matrix, lipoproteins tend to undergo oxidative and covalent modifications that stimulate the next phase of plaque development, an inflammatory response [21].

Lipoprotein modification in the subendothelium serves as an inflammatory nidus that generates numerous signals and in response, a diverse collection of mul tifunctional leukocytes may assemble, including monocytes, T cells, B cells, mast cells, dendritic cells (DCs) and neutrophils. The resultant expression of cytokines, chemokines, growth factors, proteases and migratory stimuli constitutes a focal inflammation [5-7]. Monocytes develop into tissue macrophages, ingest modified lipids, and may promote further inflammation. SMCs from the medial layer of the

Figure 1 (see following double page) Development of atherosclerosis

The focal, chronic inflammatory nidus in the arterial wall that characterizes atherosclerotic plaques begins when lipoproteins are deposited in the subendothelial tissues, where they interact with proteoglycans and other structural elements of the ECM (A). Oxidative and covalent modification of lipoproteins to variable degrees may ensue, which directly stimulates expression of adhesion molecules, cytokines, and chemokines by the overlying endothelium that in turn activate an innate immune response. As shown in B, a number of immune cell types may be recruited, notably cells of the mononuclear phagocytic lineage, but it is also noteworthy that DCs and T cells seem to be the very first immune cells present, have been seen in arteries of fetuses and young children, and may therefore precede development of plaque. DCs in particular are thought to perform sentinel functions in normal arteries; DCs appear to form a network analogous to that seen beneath the skin with Langerhans cells. Infiltrating mononuclear cells can differentiate into monocyte/macrophages or DCs. Macrophages in particular take up modified lipoproteins, but may be unable to process them fully, and may then become engorged with lipids and become foam cells (B). Abnormal breakdown of ECM components occurs, and is thought to facilitate migration of SMCs from the media into the developing plaque where they lose their contractile phenotype and may begin to secrete a number of proteins that affect plaque development. SMCs may also ingest lipids and become foam cells. Lipid-laden foam cells may die, and the presence of proinflammatory cytokines may promote apoptosis of various adjacent cells, all of which contribute to the inflammatory nidus by creating pools of modified lipids and cellular debris (C). DCs and macrophages both avidly sample their environments and present peptide fragments loaded onto MHC molecules, which when accompanied by appropriate co-stimulatory molecules activate T cells (D). Activated DCs in plaques are thought to migrate to lymph tissues, where further interactions with immune cells occur, including promoting an adaptive response and clonal expansion of T cells and B cells. These immune cells may also interact with DCs and macrophages within the plaque. The relative proportions of various subclasses of T cells found in lesions appears to be controlled by the specific types and amounts of cytokines produced in the plaque, and has very important consequences for plaque development and stability. These processes collectively increase the bulk of the lesion, creating stenoses, and an imbalance of proteolytic degradation processes that is a part of normal ECM homeostatic turnover may eventually cause structural weakening of the plaque that in turn can directly instigate plaque rupture and subsequent arterial thrombosis, the direct cause of clinical events such as myocardial infarction, stroke, and sudden cardiac death.

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  • helen
    How does atherosclerosis develop?
    7 months ago

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