Atorvastatin Active Metabolite Inhibits Oxidative Modification of Small Dense Low-Density Lipoprotein

Abstract

We tested the hypothesis that atorvastatin active metabolite (ATM), on the basis of its distinct structural features and potent antioxidant activity, preferentially inhibits lipid oxidation in human small dense low-density lipoprotein (sdLDL) and other small lipid vesicles. LDL, sdLDL, and various subfractions were isolated from human plasma by sequential ultracentrifugation, treated with ATM, atorvastatin, pravastatin, rosuvastatin, or simvastatin and were subjected to copper-induced oxidation. Lipid oxidation was measured spectrophotometrically as a function of thiobarbituric acid reactive substances formation. Similar analyses were performed in reconstituted lipid vesicles enriched in polyunsaturated fatty acids and prepared at various sizes. ATM was found to inhibit sdLDL oxidation in a dose-dependent manner. The antioxidant effects of ATM in sdLDL were 1.5 and 4.7 times greater (P < 0.001) than those observed in large buoyant LDL and very low-density lipoprotein subfractions, respectively. ATM had similar dose- and size-dependent effects in reconstituted lipid vesicles. None of these effects were reproduced by atorvastatin (parent) or any of the other statins examined in this study. These data suggest that ATM interacts with sdLDL in a specific manner that also confers preferential resistance to oxidative stress. Such interactions may reduce sdLDL atherogenicity and improve clinical outcomes in patients with cardiovascular disease.

Eicosapentaenoic Acid Inhibits Oxidation of ApoB-containing Lipoprotein Particles of Different Size In Vitro When Administered Alone or in Combination With Atorvastatin Active Metabolite Compared With Other Triglyceride-lowering Agents

“… 43 The active hydroxy metabolite of atorvastatin, in particular, is capable of directly inhibiting LDL, sdLDL, and cell membrane lipid oxidation at pharmacologic levels. 40 , 44 The chain-breaking antioxidant mechanism for atorvastatin metabolite is specifically attributed to its phenoxy moiety and is not evoked by other antioxidants such as vitamin E. 38 , 39 Clinical support for an antioxidant benefit with atorvastatin has also been reported from independent laboratories in randomized trials. 45 , 46 The antioxidant activity of atorvastatin metabolite may contribute to its anti-inflammatory benefits and account for differences in benefit beyond LDL lowering even as compared with other statins.…”

“…ApoB-containing lipoprotein fractions were isolated from the plasma of healthy volunteers by iodixanol density gradient centrifugation and adjusted to a final apolipoprotein B-100 concentration of 2 mg/mL as previously described. 40 We adapted previous methods to isolate and characterize sdLDL, LDL, and VLDL fractions using agarose gel electrophoresis. 41 …”

“…Oxidation was monitored by spectrophotometric detection of thiobarbituric acid reactive substances as previously described. 19 , 40 …”

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

“…These have an increased presence of small, dense LDL (sdLDL) particles, a common finding in insulin resistance and MetS 11,12 . The reduction of this atherogenic LDL fraction by statin treatment 13,14 could have contributed to the greater treatment benefit 10 . Atorvastatin not only reduces the number of sdLDL particles, but also inhibits, in a dose-dependent manner, lipid oxidation in human LDL particles with a preference in sdLDL 13 .…”

“…The reduction of this atherogenic LDL fraction by statin treatment 13,14 could have contributed to the greater treatment benefit 10 . Atorvastatin not only reduces the number of sdLDL particles, but also inhibits, in a dose-dependent manner, lipid oxidation in human LDL particles with a preference in sdLDL 13 . This could induce a clinical benefit both for the liver and the heart 14 .…”