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Hypercholesterolemia and inflammation in atherogenesis: two sides of the same coin
1University of California San Diego, La Jolla, CA 92093-0682, USA. dsteinberg@ucsd.edu
Insights
High cholesterol (hypercholesterolemia) is a key cause of atherosclerosis. Oxidized lipids likely trigger inflammation, suggesting both factors are crucial for preventing cardiovascular disease.
Area of Science:
- Cardiovascular Science
- Lipid Metabolism
- Inflammation Biology
Background:
- Hypercholesterolemia is a major established cause of atherosclerosis, supported by extensive experimental and clinical data.
- Evidence suggests hypercholesterolemia can be a sufficient cause in familial cases and animal models, and potentially a necessary cause at certain levels.
- Atherogenesis inherently involves inflammation, characterized by immune cell infiltration (monocytes, T-cells) into developing arterial lesions.
Purpose of the Study:
- To investigate the underlying trigger for the inflammatory component in atherogenesis.
- To explore the relationship between hypercholesterolemia, inflammation, and oxidized lipids in the context of atherosclerosis.
- To propose a unified hypothesis integrating both hypercholesterolemia and inflammation in disease development.
Main Methods:
- Review and synthesis of existing experimental, clinical, and epidemiological data on hypercholesterolemia and atherogenesis.
- Analysis of the role of inflammatory cells and their mediators in lesion development.
- Hypothesis generation based on the 'response-to-injury' paradigm, focusing on oxidized lipids as the potential 'injury'.
Main Results:
- Hypercholesterolemia is definitively linked to atherosclerosis, with strong evidence for its causative role.
- Inflammation is an integral part of atherogenesis, involving complex interactions between immune cells and artery wall components.
- Oxidized lipids within oxidized low-density lipoprotein (LDL) are proposed as a plausible 'injury' initiating the inflammatory response.
Conclusions:
- Hypercholesterolemia and inflammation are not mutually exclusive but are both critical contributors to atherogenesis.
- Oxidized lipids are a likely candidate for the 'injury' that provokes the inflammatory response in atherosclerosis.
- Effective prevention and intervention strategies for atherosclerosis must address both high cholesterol levels and the inflammatory process.
Abstract:
An abundance of experimental, clinical, and epidemiologic data capped by stunning interventional results with the statins has established hypercholesterolemia as a major causative factor in atherogenesis. In familial hypercholesterolemia and in animal models it is a sufficient cause. Some degree of hypercholesterolemia, perhaps 30-50 mg/dL, may even be a necessary cause. It is equally clear that from the very beginning atherogenesis has a strong inflammatory component, i. e., it is characterized by penetration of monocytes and of T-cells into the developing lesion. These cells, through the secretion of cytokines and growth factors, through immune responses, and through complex cross-talk with elements of the artery wall modulate the growth of the lesion and affect its stability. But inflammation has to occur in response to something. What is that something? What is the "injury" in "response-to-injury"? The case will be made that oxidized lipids in oxidized LDL or generated in response to prooxidative changes in the cells of the artery wall should be considered a plausible candidate. There is no need to consider hypercholesterolemia and inflammation as alternative hypotheses. Both are very much involved. Optimal intervention and prevention will probably require attention to both.
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