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Suchowerska, A.K. (author), Stokman, G. (author), Palmer, J.T. (author), Coghlan, P.A. (author), Pieterman, E.J. (author), Keijzer, N. (author), Lambert, G. (author), Chemello, K. (author), Jaafar, A.K. (author), Parmar, J. (author), Yan, L. (author), Tong, Y. (author), Mu, L. (author), Princen, H.M.G. (author), Bonnar, J. (author), Evison, B.J. (author)Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to...article 2022
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Pouwer, M.G. (author), Pieterman, E.J. (author), Worms, N. (author), Keijzer, N. (author), Jukema, J.W. (author), Gromada, J. (author), Gusarova, V. (author), Princen, H.M.G. (author)Atherosclerosis-related cardiovascular disease causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab-monoclonal...article 2020
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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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Berbeé, J.F.P. (author), Boon, M.R. (author), Khedoe, P.P.S.J. (author), Bartelt, A. (author), Schlein, C. (author), Worthmann, A. (author), Kooijman, S. (author), Hoeke, G. (author), Mol, I.M. (author), John, C. (author), Jung, C. (author), Vazirpanah, N. (author), Brouwers, L.P.J. (author), Gordts, P.L.S.M. (author), Esko, J.D. (author), Hiemstra, P.S. (author), Havekes, L.M. (author), Scheja, L. (author), Heeren, J. (author), Rensen, P.C.N. (author)Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by b3-adrenergic receptor stimulation protects from atherosclerosis...article 2015
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van der Tuin, S.J. (author), Kühnast, S. (author), Berbée, J. (author), Verschuren, L. (author), Pieterman, E.J. (author), Havekes, L.M. (author), van der Hoorn, J.W. (author), Rensen, P.C. (author), Jukema, J.W. (author), Princen, H.M. (author), Willems van Dijk, K. (author), Wang, Y. (author)Recently, we showed in APOE*3-Leiden.CETP mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL-C rather than by raising HDL-C. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. APOE*3-Leiden.CETP mice were fed a Western type diet...article 2015
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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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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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Kooijman, S. (author), Boon, M.R. (author), Parlevliet, E.T. (author), Geerling, J.J. (author), van de Pol, V. (author), Romijn, J.A. (author), Havekes, L.M. (author), Meurs, I. (author), Rensen, P.C.N. (author)The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE∗3...article 2014
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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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Gierman, L.M. (author), Kühnast, S. (author), Koudijs, A. (author), Pieterman, E.J. (author), Kloppenburg, M. (author), van Osch, G.J.V.M. (author), Stojanovic-Susulic, V. (author), Huizinga, T.W.J. (author), Princen, H.M.G. (author), Zuurmond. A.M., (author)Objective Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism. Methods Female...article 2014
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Khedoe, P.P.S.J. (author), Wong, M.C. (author), Wagenaar, G.T.M. (author), Plomp, J.J. (author), van Eck, M. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Hiemstra, P.S. (author), Berbée, J.F.P. (author)Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the...article 2013
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Wielinga, P.Y., (author), Harthoorn, L.F., (author), Verschuren, L., (author), Schoemaker, M.H., (author), Jouni, Z.E., (author), van, Tol, E.A.F. (author), Kleemann, R., (author), Kooistra, T. (author)Scope: This study addresses whether early life arachidonic acid (ARA)/docosahexaenoic acid (DHA) supplementation or eicosapentaenoic acid (EPA)/DHA (Omacor) supplementation affects body weight gain, lipid metabolism, and adipose tissue quantity and quality in later life in ApoE*3Leiden-transgenic mice, a humanized model for hyperlipidemia and...article 2012
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Vrins, C.L. (author), Ottenhoff, R. (author), van den Oever, K. (author), de Waart, D.R. (author), Kruyt, J.K. (author), Zhao, Y. (author), van Berkel, T.J. (author), Havekes, L.M. (author), Aerts, J.M. (author), van Eck, M. (author), Rensen, P.C. (author), Groen, A.K. (author)Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1(-/-)) mice...article 2012
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Verschuren, L. (author), Wielinga, P.Y. (author), van Duyvenvoorde, W. (author), Tijani, S. (author), Toet, K. (author), van Ommen, B. (author), Kooistra, T. (author), Kleemann, R. (author)Chronic inflammation and proatherogenic lipids are important risk factors of cardiovascular disease (CVD). Specific dietary constituents such as polyphenols and fish oils may improve cardiovascular risk factors and may have a beneficial effect on disease outcomes. We hypothesized that the intake of an antiinflammatory dietary mixture (AIDM)...article 2011
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Berbée, J.F.P. (author), Abildayeva, K. (author), Blokland, A. (author), Jansen, P.J. (author), Lütjohann, D. (author), Gautier, T. (author), Sijbrands, E. (author), Prickaerts, J. (author), Hadfoune, M. (author), Ramaekers, F.C.S. (author), Kuipers, F. (author), Rensen, P.C.N. (author)The e4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2 allele of APOC1, either alone or in...article 2011
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van Diepen, J.A. (author), Vroegrijk, I.O.C.M. (author), Berbée, J.F.P. (author), Shoelson, S.E. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Voshol, P.J. (author)Systemic inflammation is strongly involved in the pathophysiology of the metabolic syndrome, a cluster of metabolic risk factors that includes hypertriglyceridemia. Aspirin treatment lowers inflammation via inhibition of NF-?B activity but also reduces hypertriglyceridemia in humans. The aim of this study was to investigate the mechanism by...article 2011
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Eefting, D. (author), Seghers, L. (author), Grimbergen, J.M. (author), de Vries, M.R. (author), de Boer, H.C. (author), Lardenoye, J.W.H.P. (author), Jukema, J.W. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)Aims Matrix metalloproteinases (MMP) and plasminogen activator (PA)/plasmin-mediated proteolysis, especially at the cell surface, play important roles in matrix degeneration and smooth muscle cell migration, which largely contributes to vein graft failure. In this study, a novel hybrid protein was designed to inhibit both protease systems...article 2010
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Mulder, S.D. (author), van der Flier, W.M. (author), Verheijen, J.H. (author), Mulder, C. (author), Scheltens, P. (author), Blankenstein, M.A. (author), Hack, C.E. (author), Veerhuis, R. (author), TNO Kwaliteit van Leven (author)Several studies have shown that reduced amyloid-β 1-42 (Aβ {42}) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. β-site APP cleaving enzyme (BACE1) is thought to be the major β-secretase involved in Aβ production in the brain, and therefore we investigated the relation...article 2010
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Mihaescu, R. (author), Detmar, S.B. (author), Cornel, M.C. (author), van der Flier, W.M. (author), Heutink, P. (author), Hol, E.M. (author), Rikkert, M.G.M.O. (author), van Duijn, C.M. (author), Janssens, A.C.J.W. (author), TNO Kwaliteit van leven (author)Alzheimer's disease (AD) is the most prevalent form of dementia and the number of cases is expected to increase exponentially worldwide. Three highly penetrant genes (AβPP, PSEN1, and PSEN2) explain only a small number of AD cases with a Mendelian transmission pattern. Many genes have been analyzed for association with non-Mendelian AD, but the...article 2010
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TNO Kwaliteit van Leven (author), Kleemann, R. (author), van Erk, M. (author), Verschuren, L. (author), van den Hoek, A.M. (author), Koek, M. (author), Wielinga, P.Y. (author), Jie, A. (author), Pellis, L. (author), Bobeldijk-Pastorova, I. (author), Kelder, T. (author), Toet, K. (author), Wopereis, S. (author), Cnubben, N. (author), Evelo, C. (author), van Ommen, B. (author), Kooistra, T. (author)BACKGROUND: The sequence of events leading to the development of insulin resistance (IR) as well as the underlying pathophysiological mechanisms are incompletely understood. As reductionist approaches have been largely unsuccessful in providing an understanding of the pathogenesis of IR, there is a need for an integrative, time-resolved approach...article 2010