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Reduction of Cu(II) by lipid hydroperoxides: implications for the copper-dependent oxidation of low-density lipoprotein.

ABSTRACT: The Cu(II)-promoted oxidation of lipids is a lipid hydroperoxide (LOOH)-dependent process that has been used routinely to assess the oxidizability of low-density lipoprotein (LDL) in human subjects. Metal-dependent redox reactions, including those mediated by copper, have been implicated in the pathogenesis ofatherosclerosis. Despite its widespread use and possible biological significance, key elements of the mechanism are not clear. For example, although it is evident that copper acts as a catalyst, which implies a redox cycle between the Cu(II) and Cu(I) redox states, the reductants remain uncertain. In LDL these could include alpha-tocopherol, amino acid residues on the protein and LOOH. However, both alpha-tocopherol and amino acid residues are probably consumed before the most rapid phase of lipid peroxidation occurs, suggesting that another reductant must be donating electrons to Cu(II), the most likely candidate being LOOH. This role has been disputed, since LDLs nominally devoid of LOOH are still capable of reducing Cu(II) to Cu(I) and thermodynamic calculations for this reaction are not favourable. Direct investigation of the role of LOOH as reductant has not been reported and in the present study, using simple lipid systems and LDL, we have re-examined this issue using the Cu(I) chelator bathocuproine. We have shown that Cu(II) may promote lipid peroxidation in liposomes, which do not contain either protein or alpha-tocopherol, and that this is associated with reduction to Cu(I). The data also indicate that an equilibrium between free Cu(II) and LOOH exists, which only in the presence of an oxidizable substrate, i.e. unsaturated fatty acids, is shifted towards formation of Cu(I) and lipid-derived peroxyl radicals. We propose that reduction of Cu(II) by LOOH is a necessary component in sustaining the propagation of lipid peroxidation and that the formation of peroxyl radicals and their products in a lipid environment is sufficient to overcome thermodynamic barriers to the reaction.

SUBMITTER: Patel RP

PROVIDER: S-EPMC1218208 | biostudies-other | 1997 Mar

REPOSITORIES: biostudies-other

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Project description:Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. A total of 3187 patients from A to Z-TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007). The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels.

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Reduction of Cu(II) by lipid hydroperoxides: implications for the copper-dependent oxidation of low-density lipoprotein.

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