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The pathogenesis of atherosclerosis: atherogenesis and inflammation
1Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Atherosclerosis pathogenesis involves inflammation-like mechanisms, where endothelial dysfunction from risk factors like hyperlipidemia promotes plaque development. Cholesterol accumulation results from an imbalance, with high-density lipoprotein potentially aiding clearance.
Area of Science:
- Cardiovascular Biology
- Pathogenesis of Atherosclerosis
- Inflammation and Endothelial Dysfunction
Background:
- Current understanding of atherosclerosis pathogenesis highlights similarities to inflammatory processes.
- Endothelial injury, not always morphologically apparent, can result from hyperlipidemia and other risk factors, leading to plaque formation.
- Risk factors such as hyperlipidemia, hypertension, and smoking contribute to endothelial dysfunction through various mechanisms.
Purpose of the Study:
- To review current concepts in atherosclerosis pathogenesis.
- To emphasize the parallels between atherosclerosis mechanisms and inflammatory processes.
- To summarize the schematic representation of events leading to atheromatous plaque development.
Main Methods:
- Review of current scientific literature on atherosclerosis pathogenesis.
- Analysis of mechanisms involving endothelial injury, platelet and monocyte adhesion, and growth factor release.
- Examination of the role of hyperlipidemia, hypertension, smoking, and immune injury in endothelial dysfunction.
Main Results:
- Endothelial dysfunction, characterized by monocyte adhesion and increased permeability, can occur without overt endothelial injury.
- Smooth muscle cell proliferation contributes to atheromatous plaque formation, with hyperlipidemia being a significant factor, even sufficient in familial hypercholesterolemia.
- Foam cells originate from macrophages and smooth muscle cells; extracellular lipid accumulation results from insudation and foam cell degeneration.
Conclusions:
- Atherosclerosis pathogenesis involves complex interactions, including inflammation-like pathways and endothelial dysfunction.
- Cholesterol accumulation in plaques reflects an imbalance between influx and efflux, with high-density lipoprotein potentially playing a role in cholesterol removal.
- Further research is needed to fully elucidate the precise mechanisms by which all risk factors contribute to atherosclerosis susceptibility.
Abstract:
Current concepts of the pathogenesis of atherosclerosis have been reviewed, emphasizing some of the similarities of the mechanisms and events involved to those in inflammation. Figure 2 is a schematic summary of these events. Hyperlipidemia, or some component of hyperlipidemic serum, as well as other risk factors, are thought to cause endothelial injury, resulting in adhesion of platelets and/or monocytes and release of PDGF (and other growth factors), which leads to smooth muscle migration and proliferation. It is clear that endothelial injury need not be denuding, and in fact may consist of altered endothelial function (dysfunction); adhesion of monocytes, increased permeability of endothelium, and disturbances in growth control can occur without morphologically obvious endothelial injury. Hyperlipidemia, hypertension, smoking, immune injury, and other risk factors may contribute to this endothelial dysfunction in different ways and sometimes in combination. Smooth muscle cells produce large amounts of collagen, elastin, and proteoglycans and these form part of the atheromatous plaque. Hyperlipidemia contributes in a number of ways (as discussed earlier), and indeed, in the severely hypercholesterolemic patient, such as one with familial hypercholesterolemia, is alone sufficient to cause atherosclerosis in the absence of other risk factors. Foam cells of atheromatous plaques are derived both from macrophages and from smooth muscle cells; from macrophages via the beta-VLDL receptor and also possibly by way of LDL modification, recognized by the acetyl-LDL receptor (such as oxidized LDL); and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting imbalance between influx and efflux, and it is possible that high-density lipoprotein is the molecule which helps clear the cholesterol from these accumulations (134). The diagram (right) also depicts the possibility that smooth muscle proliferation may occur without endothelial injury at all. There are several postulated mechanisms for such an occurrence: loss of growth control, direct smooth muscle injury (such as by LDL), and autonomous proliferation by the mechanisms suggested by Benditt. The theoretical scheme presented is based largely on in vitro work, only partly substantiated by experimental and human studies, and does not explain the precise mechanisms by which all risk factors increase the susceptibility to atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)