Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

Rashid, Shahidur; Uffelman, Kristine D.; Barrett, P. Hugh R.; Lewis, Gary F.

doi:10.1161/01.cir.0000038303.84249.4a

Cited by 37 publications

(22 citation statements)

References 41 publications

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“…With respect to HDL, atorvastatin showed a significant decrease in its level compared with the cholesterol-fed group. This was in agreement with the study conducted by Rashid et al [24] who found that atorvastatin, in contrast to some other statins, appears to lose its HDLraising effect at high therapeutic doses (40-80 mg). This effect is attributable to the more rapid clearance of HDL apo A-1 (the major protein component of HDL) occurring in the presence of smaller increase in apoA-1 production.…”

Section: Discussionsupporting

confidence: 93%

Effects of immunomodulatory drugs on plasma inflammatory markers in a rabbit model of atherosclerosis

et al. 2010

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Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are involved. Inflammatory cytokines are implicated in the development and progression of atherosclerotic lesions. Immunomodulatory therapies have been proposed for the treatment of atherosclerosis. Therefore, the aim of this study was to investigate the systemic anti-inflammatory and immunomodulatory effects of atorvastatin, cyclosporine A (CsA), and tacrolimus (FK506) on plasma inflammatory markers in atherosclerotic rabbits. Male New Zealand rabbits were randomized into five groups each of 12 animals. Standard diet-fed group served as control, and the cholesterol-fed group received a diet supplemented with 1% cholesterol alone, cholesterol + atorvastatin, cholesterol + FK506, and cholesterol + CsA. Serum levels of lipid profile parameters (triglycerides, cholesterol, and high-density lipoprotein) were measured using colorimetric methods. Serum levels of C-reactive protein (CRP), interleukin-6 (Il-6), and interferon-gamma (INF-γ) were measured in all studied groups using ELISA techniques. Our results revealed a significant decrease (p < 0.001) in the serum levels of lipid profile parameters, CRP, Il-6, and INF-γ in atorvastatin-treated group compared with the cholesterol-fed group. On the other hand, a non-significant difference was observed for the same parameters in either FK506- or CsA-treated groups compared with the cholesterol-fed group. In conclusion, atorvastatin has a systemic anti-inflammatory role that far surpassed the cholesterol reduction effect alone. FK506 or CsA failed to suppress elevated plasma inflammatory markers. Thus, low doses of these two immunomodulating drugs could not have generalized systemic anti-inflammatory or immunosuppressive effects.

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Section: Discussionsupporting

confidence: 93%

Effects of immunomodulatory drugs on plasma inflammatory markers in a rabbit model of atherosclerosis

et al. 2010

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“…For example, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, or "statins," used primarily to decrease LDL-C levels, have been found in some in vitro studies to increase apoA-I synthesis and to have minor inhibitory effects on CETP and hepatic lipase, factors that could affect HDL metabolism (76,77). Clinically, statins generally increase plasma HDL-C concentrations by between 5% and 10%, with minor differences in HDL-increasing effects reported between various statins.…”

Section: Hdl Kinetics In Humans Administered Pharmacotherapiesmentioning

confidence: 99%

Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?

Rashid

Patterson

Lewis

2006

Journal of Lipid Research

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Plasma measurements of lipids, lipoproteins, and apolipoproteins provide information on the static levels of these fractions without providing key information on the dynamic fluxes of lipoproteins in the circulation. Kinetics studies, in contrast, provide additional information on the production and clearance rates of lipoproteins and the flow of lipids and apolipoproteins through lipoprotein fractions. This information is crucial in accurately delineating the metabolism of HDL in plasma, because plasma concentrations of HDL are the net result of the de novo production and catabolism of HDL as well as the recycling of HDL particles and the contribution to HDL from components of other lipoproteins. Studies aimed at measuring the metabolism of HDL particles have shown that HDL metabolism in vivo is complex and consists of multiple components. Kinetics studies provide a window into the metabolism of HDL, allowing us to better understand the mechanisms of HDL decrease in human conditions and the functionality of HDL particles. Here, we review the progress in our understanding of HDL metabolism derived from in vivo kinetics studies, focusing primarily on studies in humans but also reviewing key studies in animal models.-Rashid, S

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“…Similarly, although some studies suggested a beneficial effect of atorvastatin on apoAI production (Schaefer et al, 1999), enhancing transcription of apoAI mRNA by activating peroxisome proliferator-activated receptor-␣ (Martin et al, 2001), others suggested a dose-dependent effect on apoAI concentration (increase under low dose and decrease under higher dose) (Wierzbicki and Mikhailidis, 2002). No effect on apoAI kinetics (Watts et al, 2003) and concentration (Asztalos et al, 2002), or even a decrease in apoAI concentration, associated with an enhanced catabolic rate in an animal model (Rashid et al, 2002), has been reported.…”

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confidence: 99%

Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

Bach-Ngohou

Ouguerram²,

Frénais³

et al. 2005

J Pharmacol Exp Ther

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Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([ 2 H 3 ]leucineprimed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 Ϯ 19.1 versus 32 Ϯ 11.6 mg/l, p Ͻ 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 Ϯ 6.71 versus 13.37 Ϯ 6.05 mg/l, p Ͻ 0.05) and production rate (0.202 Ϯ 0.085 versus 0.119 Ϯ 0.047 mg/kg/day, p Ͻ 0.05), whereas an increase in VLDL-apoE concentration (6.44 Ϯ 2.16 before versus 9.23 Ϯ 4.02 mg/l after, p Ͻ 0.05) and production rate (0.827 Ϯ 0.367 versus 1.524 Ϯ 0.664 mg/kg/day, p Ͻ 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.

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Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

Cited by 37 publications

References 41 publications

Effects of immunomodulatory drugs on plasma inflammatory markers in a rabbit model of atherosclerosis

Effects of immunomodulatory drugs on plasma inflammatory markers in a rabbit model of atherosclerosis

Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?

Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

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