(Circulation. 1995;91:2488-2496.)
© 1995 American Heart Association, Inc.
Articles |
Atherosclerosis: Basic Mechanisms
Oxidation, Inflammation, and Genetics
From the Atherosclerosis Research Unit and the Departments of Medicine (J.A.B., M.N., A.M.F., J.S.F., L.L.D., P.A.E., A.J.L.), Pathology (J.A.B., A.D.W.), Physiology (J.S.F., L.L.D.), Biological Chemistry (P.A.E.), and Microbiology and Molecular Genetics (A.J.L.), University of California School of Medicine, Los Angeles, and the College of Letters and Sciences (A.J.L.), Los Angeles, Calif.
Correspondence to Alan M. Fogelman, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024-1736.
Abstract The clinical events resulting from atherosclerosis
are directly related to the oxidation of lipids in LDLs that become
trapped in the extracellular matrix of the subendothelial space. These
oxidized lipids activate an NF
B-like transcription factor and induce
the expression of genes containing NFB binding sites. The protein
products of these genes initiate an inflammatory response that
initially leads to the development of the fatty streak. The progression
of the lesion is associated with the activation of genes that induce
arterial calcification, which changes the mechanical characteristics of
the artery wall and predisposes to plaque rupture at sites of monocytic
infiltration. Plaque rupture exposes the flowing blood to tissue factor
in the lesion, and this induces thrombosis, which is the proximate
cause of the clinical event. There appear to be potent genetically
determined systems for preventing lipid oxidation, inactivating
biologically important oxidized lipids, and/or modulating the
inflammatory response to oxidized lipids that may explain the differing
susceptibility of individuals and populations to the development of
atherosclerosis. Enzymes associated with HDL may play an important role
in protecting against lipid oxidation in the artery wall and may
account in part for the inverse relation between HDL and risk
for atherosclerotic clinical events.
Key Words: atherosclerosis • lipids • genes • antioxidants • lipoproteins
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|
|
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|
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|
|
|
|
 |
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|
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|
|
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|
|
|
|
 |
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|
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 |
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|
|
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