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Atherosclerosis: another protein misfolding disease?
Fulvio Ursini1, Kelvin J A Davies, Matilde Maiorino
1Dept of Biological Chemistry, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy. ursini@mail.bio.unipd.it
Trends in Molecular Medicine
|July 20, 2002
Summary
Oxidatively modified low-density lipoproteins (LDL) can misfold, aggregate, and become cytotoxic, similar to amyloid proteins. This suggests atherogenesis may result from the accumulation of these harmful, misfolded lipoproteins.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Apolipoprotein B-100 (apoB-100) structure in low-density lipoproteins (LDL) is dictated by lipid interactions and metabolism.
- Oxidation of lipids in LDL alters the water-lipid interface, destabilizing the structure and leading to apoB misfolding.
- Oxidatively modified LDL, known as LDL(-), exhibits atherogenic properties and is found in vivo.
Purpose of the Study:
- To investigate the structural changes and consequences of lipid modification in LDL.
- To explore the potential link between lipoprotein misfolding and atherogenesis.
Main Methods:
- Analysis of oxidatively modified LDL (LDL(-)) isolated in vivo.
- Comparison of misfolded apoB characteristics with those of amyloidogenic proteins.
Main Results:
- Oxidized LDL leads to apoB misfolding, aggregation, and resistance to proteolysis.
- Misfolded apoB in LDL(-) shares common features with amyloidogenic proteins, including cytotoxicity.
- LDL(-) represents an in vivo model for in vitro modified LDL implicated in atherosclerosis.
Conclusions:
- Atherogenesis may be viewed as a disease driven by the accumulation of cytotoxic and pro-inflammatory misfolded lipoproteins.
- The misfolding of apoB in LDL is a critical event in the development of atherosclerosis.
- Lipoprotein misfolding shares mechanistic similarities with protein misfolding diseases like amyloidosis.