The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia

Koter, Maria; Broncel, Marlena; Chojnowska-Jezierska, J; Klikczynska, K.; Franiak, Ida

doi:10.1007/s00228-002-0507-9

Cited by 45 publications

(7 citation statements)

References 39 publications

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“…29 In humans, severe hypercholesterolemia is associated with alterations in RBC cholesterol and membrane fluidity, 30 which are improved by treatment with statins. 31 However, the majority of obese humans are not severely hypercholesterolemic, as was also the case in the present murine study. The diet we used in this study is rich in saturated fat and sucrose, leading to obesity and glucose intolerance, but the duration was not long enough to induce frank diabetes mellitus.…”

Section: Discussionsupporting

confidence: 74%

Red Blood Cell Dysfunction Induced by High-Fat Diet

et al. 2015

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Evidence is emerging that erythrocytes (red blood cells, RBCs) play an important modulatory role in the development of atherosclerosis. RBCs avidly bind proinflammatory chemokines such as monocyte chemoattractant protein-1 (MCP-1), KC/interleukin-8, and RANTES via the Duffy antigen receptor for chemokines (DARC). 6 Reversible binding to DARC may alter chemokine levels in the atherosclerotic milieu, depending on factors altering the balance of uptake versus release in RBCs traversing through plaque microvessels. Importantly, RBCs can become entrapped within atherosclerotic lesions at sites of intraplaque hemorrhage, where they are taken up by macrophages. RBC membranes are enriched in cholesterol, Background-High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC). Methods and Results-A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC-bound KC were also increased by HFD. These effects of HFD were abolished in DARC -/-mice. In RBCs from HFD-fed wild-type and DARC -/-mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into wild-type mice, RBCs from HFD-fed mice exhibited ≈3-fold increase in splenic uptake. Finally, RBCs from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation. Conclusions-RBC

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Section: Discussionsupporting

confidence: 74%

Red Blood Cell Dysfunction Induced by High-Fat Diet

et al. 2015

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“…Deletion of ABCA7 cancels cholesterol-dependent regulation of phagocytosis but not cholesterol-independent one, indicating a specific contribution of ABCA7 to phagocytosis. Lowering cholesterol reportedly increases membrane fluidity and results in enhancement of phagocytosis [44, 45], so that ABCA7 may contribute to this process.…”

Section: Discussionmentioning

confidence: 99%

HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7

et al. 2011

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We recently reported that the endogenous ATP-binding cassette transporter (ABC) A7 strongly associates with phagocytosis, being regulated by sterol regulatory element binding protein 2. We therefore examined the effect of statins on phagocytosis in vitro and in vivo through the SREBP-ABCA7. Phagocytosis was found to be enhanced by pravastatin, rosuvastatin and simvastatin and cyclodextrin in J774 macrophages, as cellular cholesterol was reduced and expressions of the cholesterol-related genes were modulated, including an increase of ABCA7 mRNA and decrease of ABCA1 mRNA. Conversely, knock-down of ABCA7 expression by siRNA ablated enhancement of phagocytosis by statins. In vivo, pravastatin enhanced phagocytosis in wild-type mice, but not in ABCA7-knockout mice. We thus concluded that statins enhance phagocytosis through the SREBP-ABCA7 pathway. These findings provide a molecular basis for enhancement of the host-defense system by statins showing that one of their “pleiotropic” effects is in fact achieved through their reaction to a primary target.

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“…We have previously demonstrated that de novo cholesterol synthesis is elevated in the lungs of Cftr -/- mice [3]. Evidence does suggest that membrane cholesterol content can be regulated by de novo synthesis [9,10]. Koter et al demonstrate that statin treatment reduces membrane cholesterol content in erythrocytes from 2.24 +/- 1.69 to 1.17 +/- 0.75 mg cholesterol/mg protein, a 47% reduction [9].…”

Section: Introductionmentioning

confidence: 99%

“…Evidence does suggest that membrane cholesterol content can be regulated by de novo synthesis [9,10]. Koter et al demonstrate that statin treatment reduces membrane cholesterol content in erythrocytes from 2.24 +/- 1.69 to 1.17 +/- 0.75 mg cholesterol/mg protein, a 47% reduction [9]. It is possible that increased membrane cholesterol in CF plasma membrane is related to increased de novo cholesterol synthesis.…”

Section: Introductionmentioning

confidence: 99%

Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis

et al. 2010

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BackgroundPrevious observations demonstrate that Cftr-null cells and tissues exhibit alterations in cholesterol processing including perinuclear cholesterol accumulation, increased de novo synthesis, and an increase in plasma membrane cholesterol accessibility compared to wild type controls. The hypothesis of this study is that membrane cholesterol accessibility correlates with CFTR genotype and is in part influenced by de novo cholesterol synthesis.MethodsElectrochemical detection of cholesterol at the plasma membrane is achieved with capillary microelectrodes with a modified platinum coil that accepts covalent attachment of cholesterol oxidase. Modified electrodes absent cholesterol oxidase serves as a baseline control. Cholesterol synthesis is determined by deuterium incorporation into lipids over time. Incorporation into cholesterol specifically is determined by mass spectrometry analysis. All mice used in the study are on a C57Bl/6 background and are between 6 and 8 weeks of age.ResultsMembrane cholesterol measurements are elevated in both R117H and ΔF508 mouse nasal epithelium compared to age-matched sibling wt controls demonstrating a genotype correlation to membrane cholesterol detection. Expression of wt CFTR in CF epithelial cells reverts membrane cholesterol to WT levels further demonstrating the impact of CFTR on these processes. In wt epithelial cell, the addition of the CFTR inhibitors, Gly H101 or CFTRinh-172, for 24 h surprisingly results in an initial drop in membrane cholesterol measurement followed by a rebound at 72 h suggesting a feedback mechanism may be driving the increase in membrane cholesterol. De novo cholesterol synthesis contributes to membrane cholesterol accessibility.ConclusionsThe data in this study suggest that CFTR influences cholesterol trafficking to the plasma membrane, which when depleted, leads to an increase in de novo cholesterol synthesis to restore membrane content.

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The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia

Cited by 45 publications

References 39 publications

Red Blood Cell Dysfunction Induced by High-Fat Diet

Red Blood Cell Dysfunction Induced by High-Fat Diet

HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7

Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis

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