Abstract Background Elevated lipoprotein(a) Lp(a) levels are causally and independently associated with increased cardiovascular risk. Other atherogenic particles include small dense LDL (sdLDL) and triglyceride-rich lipoproteins (e.g. VLDL). Lp(a) stimulates inflammation and macrophage uptake due to its oxidized phospholipid (oxPL) content. Unlike other statins, atorvastatin is metabolized by cytochromes to an active hydroxylated metabolite that have free radical scavenging properties. Purpose We compared the effects of 2-o-hydroxy atorvastatin (atorva(m)) to other statins in active form – namely pitavastatin, rosuvastatin, pravastatin, and simvastatin – on rates of lipoprotein oxidation in plasma samples enriched with Lp(a), sdLDL and VLDL. We also tested these agents in non-modified LDL and compared with the lipophilic antioxidant probucol. Methods Lp(a) was enriched to 62% of total ApoB-containing particles (remaining 38% was LDL) from patients with elevated levels by isopycnic centrifugation. Lipoprotein fractions containing matching enrichments of Lp(a)-, sdLDL-, VLDL- and LDL were incubated at 37°C for 30 min with equimolar statin or probucol (10 µM). Samples were also incubated with multiple doses of atorva(m) (1.0-10.0 µM). Samples were then subjected to copper sulfate-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA). Results Lp(a)-enriched plasma underwent the most rapid oxidation as evidenced by 44% of the total oxidized lipid produced after 0.5 h compared with 26%, 7%, and 15% for sdLDL, VLDL and LDL enrichments, respectively (p0.05). Atorva(m) significantly inhibited Lp(a), sdLDL, VLDL oxidation in a time- and dose-dependent manner. Compared with the other statins, only atorva(m) significantly reduced MDA formation in each lipoprotein fraction at the time point corresponding to peak lipoprotein oxidation; this corresponded to 59%, 70%, 75%, and 78% reductions in MDA levels in Lp(a)-, sdLDL-, VLDL-, and LDL-enriched fraction, respectively (all p0.001). The highest concentration of atorva(m) (10 µM) exhibited lipid antioxidant activity persisted at all time points. Probucol exhibited significant antioxidant activity in each fraction as expected, though to a lesser extent than atorva(m) (p0.05). Conclusions Atorva(m) inhibited oxidation of Lp(a) enriched plasma in a time- and dose-dependent fashion compared to other widely used statins due to free radical scavenging properties. The antioxidant activity extended to other atherogenic ApoB particles including sdLDL. The potent antioxidant actions of atorvastatin active metabolites may reduce the atherogenicity of Lp(a) in patients with elevated Lp(a) concentrations independent of changes in lipid levels.
Sherratt et al. (Sat,) studied this question.