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Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in apoE/LDLR double knockout mice

Hu, L. (author), Boesten, L.S.M. (author), May, P. (author), Herz, J. (author), Bovenschen, N. (author), Huisman, M.V. (author), Berbée, J.F.P. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Tamsma, J.T. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins. METHODS AND RESULTS - We generated...

article 2006

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Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

den Boer, M.A.M. (author), Berbée, J.F.P. (author), Reiss, P. (author), van der Valk, M. (author), Voshol, P.J. (author), Kuipers, F. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Romijn, J.A. (author), Gaubius Instituut TNO (author)

Objective - The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. Methods and Results - Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35...

article 2006

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Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice

Duivenvoorden, I. (author), Voshol, P.J. (author), Rensen, P.C.N. (author), van Duyvenvoorde, W. (author), Romijn, J.A. (author), Emeis, J.J. (author), Havekes, L.M. (author), Nieuwenhuizen, W.F. (author), TNO Kwaliteit van Leven (author)

Background: The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. Objective: Our goal was to determine the effect of...

article 2006

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Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo

Schepers, A. (author), Eefting, D. (author), Bonta, P.I. (author), Grimbergen, J.M. (author), de Vries, M.R. (author), van Weel, V. (author), de Vries, C.J. (author), Egashira, K. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - Because late vein graft failure is caused by intimal hyperplasia (IH) and accelerated atherosclerosis, and these processes are thought to be inflammation driven, influx of monocytes is one of the first phenomena seen in IH, we would like to provide direct evidence for a role of the MCP-1 pathway in the development of vein graft...

article 2006

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Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice

Boesten, L.S.M. (author), Zadelaar, A.S.M. (author), van Nieuwkoop, A. (author), Hu, L. (author), Jonkers, J. (author), van de Water, B. (author), Gijbels, M.J.J. (author), van der Made, I. (author), de Winther, M.P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), TNO Kwaliteit van Leven (author)

The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE...

article 2006

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Cholesterol 7α-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol

Post, S.M. (author), Groenendijk, M. (author), van der Hoogt, C.C. (author), Fievet, C. (author), Luc, G. (author), Hoekstra, M. (author), Princen, H.M.G. (author), Staels, B. (author), Rensen, P.C.N. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (Cyp7a1) catalyzes the rate-limiting step...

article 2006

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Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice

van Weel, V. (author), de Vries, M. (author), Voshol, P.J. (author), Verloop, R.E. (author), Eilers, P.H.C. (author), van Hinsbergh, V.W.M. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - Collateral artery development (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease, may be deregulated by vascular risk factors, eg, diabetes or hypercholesterolemia. Here, we compared the effects of either disturbed glucose metabolism or disturbed lipid metabolism on arteriogenesis. METHODS...

article 2006

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Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL

TNO Kwaliteit van Leven (author), Westerterp, M. (author), de Haan, W. (author), Berbée, J.F.P. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)

Previous studies have shown that overexpression of human apolipoprotein C-I (apoC-I) results in moderate hypercholesterolemia and severe hypertriglyceridemia in mice in the presence and absence of apoE. We assessed whether physiological endogenous apoC-I levels are sufficient to modulate plasma lipid levels independently of effects of apoE on...

article 2006

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Anti-atherosclerotic effect of amlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice

TNO Kwaliteit van Leven (author), Trion, A. (author), Maat, M.de (author), Jukema, W. (author), Maas, A. (author), Offerman, E. (author), Havekes, L. (author), Szalai, A. (author), Laarse, A.V.D. (author), Princen, H. (author), Emeis, J. (author)

We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either...

article 2006

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Apolipoprotein AV: Low concentration, high impact

Rensen, P.C.N. (author), van Dijk, K.W. (author), Havekes, L.M. (author), TNO Kwaliteit van Leven (author)

Chemicals / CAS: lipoprotein lipase, 83137-80-8, 9004-02-8; APOA5 protein, human; Apolipoproteins A; Apolipoproteins; Triglycerides

article 2005

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Response of apolipoprotein E*3-Leiden transgenic mice to dietary fatty acids: Combining liver proteomics with physiological data

de Roos, B. (author), Duivenvoorden, I. (author), Rucklidge, G. (author), Reid, M. (author), Ross, K. (author), Lamers, R.J.A.N. (author), Voshol, P.J. (author), Havekes, L.M. (author), Teusink, B. (author), TNO Kwaliteit van Leven (author)

article 2005

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Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice

Delsing, D.J.M. (author), Post, S.M. (author), Groenendijk, M. (author), Solaas, K. (author), van der Boom, H. (author), van Duyvenvoorde, W. (author), de Wit, E.C.M. (author), Bloks, V.W. (author), Kuipers, F. (author), Havekes, L.M. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (O [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w)...

article 2005

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No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice

Trion, A. (author), de Maat, M.P.M. (author), Jukema, J.W. (author), van der Laarse, A. (author), Maas, M.C. (author), Offerman, E.H. (author), Havekes, L.M. (author), Szalai, A.J. (author), Princen, H.M.G. (author), Emeis, J.J. (author), TNO Kwaliteit van Leven (author)

Objective - C-reactive protein (CRP) has been associated with risk of cardiovascular disease. It is not clear whether CRP is causally involved in the development of atherosclerosis. Mouse CRP is not expressed at high levels under normal conditions and increases in concentration only several-fold during an acute phase response. Because the...

article 2005

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Apolipoproteins modulate the inflammatory response to lipopolysaccharide

Berbée, J.F.P. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), TNO Kwaliteit van Leven (author)

An increasing body of evidence demonstrates a close interplay between lipoprotein metabolism and sepsis. Sepsis results in an increase of plasma triglycerides within VLDL as a consequence of an enhanced hepatic VLDL production and/or inhibited peripheral and hepatic VLDL clearance. In contrast, sepsis decreases plasma cholesterol within LDL and...

article 2005

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Tumor necrosis factor-α plays an important role in restenosis development

Monraats, P.S. (author), Pires, N.M.M. (author), Schepers, A. (author), Agema, W.R.P. (author), Boesten, L.S.M. (author), de Vries, M.R. (author), Zwinderman, A.H. (author), de Maat, M.P.M. (author), Doevendans, P.A.F.M. (author), de Winter, R.J. (author), Tio, R.A. (author), Waltenberger, J. (author), 't Hart, L.M. (author), Frants, R.R. (author), Quax, P.H.A. (author), van Vlijmen, B.J.M. (author), Havekes, L.M. (author), van der Laarse, A. (author), van der Wall, E.E. (author), Jukema, J.W. (author), TNO Kwaliteit van Leven (author)

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFα, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER)...

article 2005

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Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice

TNO Kwaliteit van Leven (author), Gautier, T. (author), Masson, D. (author), Jong, M.C. (author), Pais De Barros, J.P. (author), Duverneuil, L. (author), Le Guern, N. (author), Deckert, V. (author), Dumont, L. (author), Bataille, A. (author), Zak, Z. (author), Jiang, X.C. (author), Havekes, L.M. (author), Lagrost, L. (author)

ApoCI (apolipoprotein CI) is a potent inhibitor of plasma CETP [CE (cholesteryl ester) transfer protein]. The relevance of apoCI overexpression as a method for CETP blockade in vivo was addressed in the present study in CETPTg/apoCITg mice (mice expressing both human CETP and apoCI). Despite a significant reduction in specific CETP activity in...

article 2005

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Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice

Verschuren, L. (author), Kleemann, R. (author), Offerman, E.H. (author), Szalai, A.J. (author), Emeis, S.J. (author), Princen, H.M.G. (author), Kooistra, T. (author), TNO Kwaliteit van Leven (author)

Objective - To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. Methods and Results - ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet...

article 2005

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Metabolomics in the context of systems biology: Bridging Traditional Chinese Medicine and molecular pharmacology

Wang, M. (author), Lamers, R.J.A.N. (author), Korthout, H.A.A.J. (author), van Nesselrooij, J.H.J. (author), Witkamp, R.F. (author), van der Heijden, R. (author), Voshol, P.J. (author), Havekes, L.M. (author), Verpoorte, R. (author), van der Greef, J. (author), TNO Kwaliteit van Leven (author)

The introduction of the concept of systems biology, enabling the study of living systems from a holistic perspective based on the profiling of a multitude of biochemical components, opens up a unique and novel opportunity to reinvestigate natural products. In the study of their bioactivity, the necessary reductionistic approach on single active...

article 2005

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ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

TNO Kwaliteit van Leven (author), Gerritsen, G. (author), Rensen, P.C.N. (author), Kypreos, K.E. (author), Zannis, V.I. (author), Havekes, L.M. (author), van Dijk, K.W. (author)

Adenovirus-mediated overexpression of human apolipoprotein E (apoE) induces hyperlipidemia by stimulating the VLDL-triglyceride (TG) production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Because apoC-III is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3 deficiency might prevent the hyperlipidemia induced by...

article 2005

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Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

TNO Kwaliteit van Leven (author), Espirito Santo, S.M.S. (author), Rensen, P.C.N. (author), Goudriaan, J.R. (author), Bensadoun, A. (author), Bovenschen, N. (author), Voshol, P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author)

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the...

article 2005