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Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase

Simic, B. (author), Mocharla, P. (author), Crucet, M. (author), Osto, E. (author), Kratzer, A. (author), Stivala, S. (author), Kühnast, S. (author), Speet, T. (author), Doycheva, P. (author), Princen, H.M.G. (author), van der Hoorn, J.W.A. (author), Jukema, J.W. (author), Giral, H. (author), Tailleux, A. (author), Landmesser, U. (author), Syaels, B. (author), Lüscher, T.F. (author)

Background and aims. High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase...

article 2017

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The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice

Landlinger, C. (author), Pouwer, M.G. (author), Juno, C. (author), van der Hoorn, J.W.A. (author), Pieterman, E.J. (author), Jukema, J.W. (author), Staffler, G. (author), Princen, H.M.G. (author), Galabova, G. (author)

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher...

article 2017

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Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

Kühnast, S. (author), van der Tuin, S.J.L. (author), van der Hoorn, J.W.A. (author), van Klinken, J.B. (author), Simic, B. (author), Pieterman, E. (author), Havekes, L.M. (author), Landmesser, U. (author), Lüscher, T.F. (author), van Dijk, K.W. (author), Rensen, P.C.N. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Background The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to...

article 2015

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Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes

Liang, W. (author), Verschuren, L. (author), Mulder, P. (author), van der Hoorn, J.W.A. (author), Verheij, J. (author), van Dam, A.D. (author), Boon, M.R. (author), Princen, H.M.G. (author), Havekes, L.M. (author), Kleemann, R. (author), van den Hoek, A.M. (author)

BACKGROUND AND PURPOSE: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested...

article 2015

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Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raisingA systematic review and meta-analysis of relevant preclinical studies and clinical trials

Kühnast, S. (author), Fiocco, M. (author), van der Hoorn, J.W.A. (author), Princen, H.M.G. (author), Jukema, J.W. (author)

Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This...

article 2015

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PET imaging of disease progression and treatment effects in the experimental autoimmune encephalomyelitis rat model

de Paula Faria, D. (author), Vlaming, M.L.H. (author), Copray, S.C.V.M. (author), Tielen, F. (author), Anthonijsz, H.J.A. (author), Sijbesma, J.W.A. (author), Buchpiguel, C.A. (author), Dierckx, R.A.J.O. (author), van der Hoorn, J.W.A. (author), de Vries, E.F.J. (author)

The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET imaging may be a useful noninvasive technique for...

article 2014

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APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome

van den Hoek, A.M. (author), van der Hoorn, J.W.A. (author), Maas, A.C. (author), van den Hoogen, R.M. (author), van Nieuwkoop, A. (author), Droog, S. (author), Offerman, E.H. (author), Pieterman, E.J. (author), Havekes, L.M. (author), Princen, H.M.G. (author)

Aims: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. Methods: Male obese, IR and...

article 2014

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RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice

Louwe, M.C. (author), Karper, J.C. (author), de Vries, M.R. (author), Nossent, A.Y. (author), Bastiaansen, A.J.N.M. (author), van der Hoorn, J.W.A. (author), Willems Van Dijk, K. (author), Rensen, P.C.N. (author), Steendijk, P. (author), Smit, J.W.A. (author), Quax, P.H.A. (author)

Background Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by...

article 2014

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P430RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice

Louwe, M.C. (author), Karper, J.C. (author), de Vries, M.R. (author), Bastiaansen, A.J.N.M. (author), van der Hoorn, J.W.A. (author), Willems Van Dijk, K. (author), Rensen, P.C.N. (author), Steendijk, P. (author), Smit, J.W.A. (author), Quax, P.H.A. (author)

Purpose: Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signalling domain that competitively inhibits TLR4-signalling. Thus, we hypothesized that RP105 deficiency, by...

article 2014

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PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

Ason, B. (author), van der Hoorn, J.W.A. (author), Chan, J. (author), Lee, E. (author), Pieterman, E.J. (author), Nguyen, K.K. (author), Di, M. (author), Shetterly, S. (author), Tang, J. (author), Yeh, W.C. (author), Schwarz, M. (author), Jukema, J.W. (author), Scott, R. (author), Wasserman, S.M. (author), Princen, H.M.G. (author), Jackson, S. (author)

LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower...

article 2014

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Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin

Kühnast, S. (author), van der Hoorn, J.W.A. (author), Pieterman, E.J. (author), van den Hoek, A.M. (author), Sasiela, W.J. (author), Gusarova, V. (author), Peyman, A. (author), Schäfer, H.L. (author), Schwahn, U. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE∗3Leiden. CETP mice. Mice received a Western-type diet and were treated with...

article 2014

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Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE * 3-Leiden.CETP mice

Berbée, J.F.P. (author), Wong, M.C. (author), Wang, Y. (author), van der Hoorn, J.W.A. (author), Khedoe, P.P.S.J. (author), van Klinken, J.B. (author), Mol, I.M. (author), Hiemstra, P.S. (author), Tsikas, D. (author), Romijn, J.A. (author), Havekes, L.M. (author), Princen, H.M.G. (author), Rensen, P.C.N. (author)

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*. 3...

article 2013

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Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol

Kühnast, S. (author), Louwe, M.C. (author), Heemskerk, M.M. (author), Pieterman, E.J. (author), van Klinken, J.B. (author), van den Berg, S.A.A. (author), Smit, J.W.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), van der Hoorn, J.W.A. (author), Princen, H.M.G. (author), Jukema, J.W. (author)

Objective:Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination...

article 2013

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Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden.CETP transgenic mice with or without treatment with atorvastatin

Kühnast, S. (author), van der Hoorn, J.W.A. (author), van den Hoek, A.M. (author), Havekes, L.M. (author), Liau, G. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Objective: Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to evaluate the antiatherosclerotic and plaque...

article 2012

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Validation of interventional fiber optic spectroscopy with MR Spectroscopy, MAS-NMR spectroscopy, high-performance thin-layer chromatography, and histopathology for accurate hepatic fat quantification

Nachabé, R. (author), van der Hoorn, J.W.A. (author), van de Molengraaf, R. (author), Lamerichs, R. (author), Pikkemaat, J. (author), Sio, C.F. (author), Hendriks, B.H.W. (author), Sterenborg, H.J.C.M. (author)

Objectives: To validate near-infrared (NIR)-based optical spectroscopy measurements of hepatic fat content using a minimally invasive needle-like probe with integrated optical fibers, enabling real-time feedback during percutaneous interventions. The results were compared with magnetic resonance spectroscopy (MRS) as validation and with...

article 2012

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Niacin reduces plasma CETP levels by diminishing liver macrophage content in CETP transgenic mice

Li, Z. (author), Wang, Y. (author), van der Sluis, R.J. (author), van der Hoorn, J.W.A. (author), Princen, H.M.G. (author), van Eck, M. (author), van Berkel, T.J.C. (author), Rensen, P.C.N. (author), Hoekstra, M. (author)

The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of CETP. Since liver macrophages contribute to hepatic CETP expression, we investigated the role of macrophages in the CETP-lowering effect of niacin in mice. In vitro studies showed that niacin does not directly attenuate CETP expression...

article 2012

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Gender-dependent effects of high-fat lard diet on cardiac function in C57Bl/6J mice

Louwe, M.C. (author), van der Hoorn, J.W.A. (author), van den Berg, S.A.A. (author), Wouter Jukema, J. (author), Romijn, J.A. (author), van Dijk, K.W. (author), Rensen, P.C.N. (author), Smit, J.W.A. (author), Steendijk, P. (author)

Increased availability of fatty acids released from insulin-resistant adipose tissue may lead to excess fatty acid uptake in nonadipose organs, including the heart. Accumulation of toxic fatty acid intermediates may affect cardiac function. Our aim was to identify to which extent high-fat diet feeding leads to alterations in cardiac function and...

article 2012

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Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels

van der Hoorn, J.W.A. (author), Lindén, D. (author), Lindahl, U. (author), Bekkers, M.E.A. (author), Voskuilen, M. (author), Nilsson, R. (author), Oscarsson, J. (author), Lindstedt, E.L. (author), Princen, H.M.G. (author)

BACKGROUND AND PURPOSE Liver X receptor (LXR) agonists are atheroprotective but often induce hypertriglyceridaemia and liver steatosis. We investigated the effect of a novel high-affinity LXR activator, AZ876, on plasma lipids, inflammation and atherosclerosis, and compared the effects with another LXR agonist, GW3965. EXPERIMENTAL APPROACH APOE...

article 2011

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Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice

TNO Kwaliteit van Leven (author), Bijland, S. (author), Pieterman, E.J. (author), Maas, A.C.E. (author), van der Hoorn, J.W.A. (author), van Erk, M.J. (author), van Klinken, J.B. (author), Havekes, L.M. (author), van Dijk, K.W. (author), Princen, H.M.G. (author), Rensen, P.C.N. (author)

The peroxisome proliferator-activated receptor alpha (PPARalpha) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are...

article 2010

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The dual PPARα/γ agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOE*3Leiden.CETP transgenic mice

van der Hoorn, J.W.A. (author), Jukema, J.W. (author), Havekes, L.M. (author), Lundholm, E. (author), Camejo, G. (author), Rensen, P.C.N. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

Background and purpose: We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)α/γ agonist on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. Experimental approach: E3L.CETP mice were fed a high-cholesterol diet for 11 weeks to...

article 2009