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Pathophysiology of the atherogenic process
C J Schwartz1, J L Kelley, R M Nerem
1Department of Pathology, University of Texas Health Science Center, San Antonio 78284-7750.
Insights
Atherosclerosis involves inflammation and arterial wall healing. Oxidative modification of low-density lipoprotein (LDL) drives foam cell formation, but antioxidants like probucol may inhibit this process.
Area of Science:
- Cardiovascular Science
- Pathophysiology
- Inflammation Biology
Background:
- Atherosclerosis is a complex inflammatory disease involving arterial wall responses to injury within a hyperlipidemic environment.
- Understanding the multifactorial pathophysiology of atherogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To review key aspects of atherogenesis, focusing on hemodynamic stresses, monocyte recruitment, macrophage scavenger receptor pathways, and lipoprotein modification.
- To highlight the role of oxidized low-density lipoprotein (LDL) in foam cell formation and plaque development.
- To discuss the potential of antioxidant therapy in mitigating atherosclerosis.
Main Methods:
- Review of existing literature on the pathophysiology of atherosclerosis.
- Discussion of the influence of shear stress on endothelial cells.
- Analysis of monocyte recruitment mechanisms and macrophage scavenger receptor pathways.
- Examination of lipoprotein modification, particularly LDL oxidation.
Main Results:
- Hemodynamic shear stress influences endothelial cell properties and lesion development.
- Monocyte recruitment to the intima involves chemoattractants like oxidized LDL.
- Macrophage scavenger receptors mediate the uptake of modified LDL, leading to foam cell formation.
- Oxidative modification of LDL is a key driver of foam cell formation and plaque progression.
Conclusions:
- Atherogenesis is an inflammatory process significantly influenced by hemodynamic factors and lipoprotein metabolism.
- Oxidized LDL uptake via scavenger receptors is a critical, non-down-regulating mechanism in foam cell formation.
- The antioxidant probucol demonstrates potential in retarding atherogenesis by preventing LDL oxidation, independent of cholesterol levels.
Abstract:
Atherosclerosis is conceptually defined as the result of a multiplicity of interactive cascades among injurious stimuli and the healing responses of the arterial wall, occurring concurrently within a hyperlipidemic environment. In this discussion, the inflammatory nature of the disease is emphasized. Four aspects of the pathophysiology of atherogenesis are addressed: (1) The role(s) of fluid mechanical or hemodynamic stresses in the focal initiation and/or augmentation of lesions is discussed in terms of the influence of shear stress on endothelial cellular geometry, compliance, membrane anisotropy (r), low-density lipoprotein (LDL)-receptor expression, intracellular potential and replication; (2) mechanisms of blood monocyte recruitment to the arterial intima, including the roles of chemoattractants such as smooth muscle cell-derived chemotactic factor and oxidized LDL; (3) the alternate or "scavenger" receptor pathway of the macrophage and its pivotal roles in foam cell formation and plaque pathogenesis; and (4) the emerging significance of various lipoprotein modifications, and in particular, the oxidative modification of LDL, which facilitates the uptake of the cytotoxic oxidized LDL via the scavenger receptor, thus providing a non-down-regulating mechanism for foam cell formation and plaque development. Evidence indicates that the antioxidant drug probucol prevents the oxidative modification of LDL, thereby retarding atherogenesis independently of cholesterol reduction.