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Van Der Giet M.,Medizinische Klinik IV Nephrology | Tolle M.,Medizinische Klinik IV Nephrology | Pratico D.,Temple University | Lufft V.,Nephrologisches Zentrum Rendsburg Eckernforde | And 4 more authors.
Journal of Molecular Medicine | Year: 2010

End-stage renal disease (ESRD) patients exhibit increased in vivo oxidative stress conceivably contributing to cardiovascular mortality. The type IIA secretory phospholipase A2 (sPLA2) has proatherogenic activity. We explored the hypothesis that sPLA2 contributes to oxidative stress generation and endothelial dysfunction in ESRD patients and transgenic (tg) mice. Patients with ESRD had increased in vivo oxidative stress as assessed by plasma isoprostane levels (p<0.001). Active sPLA2 in plasma was substantially increased compared with healthy controls (1,156±65 versus 184±5 ng/dL, p<0.001) and correlated with plasma isoprostanes (r=0.61, p<0.001). Correspondingly, human sPLA 2 tg mice display increased generation of reactive oxygen species within aortic vascular smooth muscle cells, leading to severe endothelial dysfunction (maximal vasodilation in response to 10 μmol/L acetylcholine, sPLA2 36±8%, controls 80±2% of phenylephrine-induced vasoconstriction). Increased vascular oxidative stress in sPLA2 tg mice is dependent on the induction of vascular cyclooxygenase (COX)2 expression. Conversely, ESRD patients show increased formation of COX2-derived prostaglandins (p<0.05) correlated with plasma sPLA2 (r=0.71, p<0.05). Our data indicate that increased expression of sPLA2 might represent a novel causative risk factor contributing to the increased cardiovascular disease morbidity and mortality in ESRD. © 2009 Springer-Verlag. Source


Annema W.,Center for Liver | Annema W.,Top Institute Food and Nutrition | Nijstad N.,Center for Liver | Tolle M.,Medizinische Klinik IV Nephrology | And 6 more authors.
Journal of Lipid Research | Year: 2010

Atherosclerosis is linked to infl ammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol effl ux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute infl ammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [3 H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol effl ux toward plasma and HDL were signifi cantly decreased (P < 0.001). In mice, acute infl ammation (75 μg/mouse lipopolysaccharide) decreased [3 H] cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (-84%) and neutral sterols (-79%, each P < 0.001). In the absence of systemic infl ammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A2 (sPLA2, transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (-36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by infl ammation. In conclusion, our data demonstrate that acute infl ammation impairs cholesterol effl ux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during infl ammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in infl ammation. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc. Source


De Boer J.F.,University of Groningen | Annema W.,University of Groningen | Annema W.,Top Institute Food and Nutrition | Schreurs M.,University of Groningen | And 6 more authors.
Journal of Lipid Research | Year: 2012

Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels (P < 0.05), particularly within HDL, and increased hepatic cholesterol content (P < 0.001). T1DM resulted in increased bile flow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5- fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM (P < 0.001). Mass fecal BA output was significantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [ 3H] cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM (P < 0.05), mainly due to reduced tracer excretion within BA (P < 0.05). In vitro experiments revealed unchanged cholesterol efflux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) (P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular disease in T1DM. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source


Nijstad N.,University of Groningen | De Boer J.F.,University of Groningen | Lagor W.R.,University of Pennsylvania | Toelle M.,Medizinische Klinik IV Nephrology | And 5 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2011

Apolipoprotein (apo) O is a newly discovered apolipoprotein preferentially contained within HDL; however, currently, no data are available on the (patho)physiological effects of apoO. Therefore, the present study assessed the impact of apoO overexpression on (i) plasma lipids and lipoproteins as well as on (ii) HDL functionality. Human apoO was overexpressed by means of recombinant adenovirus (AdhapoO) in human apoA-I transgenic mice, a humanized mouse model of HDL metabolism. AdhapoO substantially increased apoO in plasma and within HDL. However, plasma triglycerides, phospholipids, total cholesterol and HDL cholesterol did not change. HDL size distribution, lipid composition and the apoA-I and the apoO distribution over the different HDL fractions separated by FPLC remained unaltered. Furthermore, enrichment of HDL with apoO did not impact on HDL functionality assessed in four independent ways, namely (i) stimulation of cholesterol efflux from macrophage foam cells, (ii) protection against LDL oxidation, (iii) anti-inflammatory activity on endothelial cells, and (iv) induction of vasodilation in isolated aortic rings ex vivo as a measure of stimulating vascular NO production. These results demonstrate that although overexpression of apoO results in a substantial enrichment of HDL particles with this novel apolipoprotein, apoO does not impact the plasma lipoprotein profile or HDL functionality. © 2011 Elsevier B.V. Source

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