Atherogenesis, the oxidative LDL modification hypothesis revisited

Abstract

The commonly-accepted "oxidized LDL hypothesis of atherogenesis" is based on a large number of indirect evidence that shows that oxidatively-modified LDL plays a role in atherogenesis. Yet, the exact role is not clear. Some researchers think that oxidatively modified biomolecules initiate atherogenesis; others believe that they "only" promote this multifactorial process. Regardless of the exact mechanism responsible for the effect of peroxidation on atherogenesis, the "oxidative theory of AS" is apparently inconsistent with the results of meta-analysis, in which (the "expected") significant correlation between CVD and oxidative stress (OS) was found only when the OS was evaluated on the basis of the plasma concentrations of malondialdehyde (MDA), often based on the concentration of thiobarbituric acid reactive substances (TBARS). Notably, even this association is questionable due to 1) poor reliability of the laboratory assay of MDA and 2) possible publication bias. Hence, it appears that the commonly accepted paradigm regarding the role of oxidative damage in the pathogenesis of CVD has been overestimated. Furthermore, the hypothesis is apparently inconsistent with the disappointing results of most of the clinical trials that were designed to reduce OS by means of supplementation of antioxidants, mostly vitamin E. These apparent inconsistencies do not contradict the oxidative modification hypothesis of AS. The source of the apparent contradictions is probably the oversimplified considerations on which the predictions have been based. Many reasonable arguments can be raised to explain the apparent contradictions, which means that our current knowledge is insufficient to test the relationship of oxidative stress to cardiovascular disease.[85] Tynkkynen, T., Mursu, J., Nurmi, T., Tuppurainen, K., Laatikainen, R. and Soininen, P. (2012) NMR protocol for determination of oxidation susceptibility of serum lipids and application of the protocol to a chocolate study. Metabolomics,8,[386][387][388][389][390][391][392][393][394][395][396][397][398]