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IL-1β inhibition combined with cholesterol-lowering therapies decreases synovial lining thickness and spontaneous cartilage degeneration in a humanized dyslipidemia mouse model

van Gemert, Y. (author), Kruisbergen, N.N.L. (author), Blom, A.B. (author), van den Bosch, M.H.J. (author), van der Kraan, P.M. (author), Pieterman, E.J. (author), Princen, H.M.G. (author), van Lent, P.L.E.M. (author)

Introduction: Both systemic inflammation and dyslipidemia contribute to osteoarthritis (OA) development and have been suggested as a possible link between metabolic disease and OA development. Recently, the CANTOS trial showed a reduction in knee and hip replacements after inhibition of IL-1β in patients with a history of cardiovascular disease...

article 2023

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A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

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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Chronic Oral Administration of Mineral Oil Compared With Corn Oil: Effects on Gut Permeability and Plasma Inflammatory and Lipid Biomarkers

Pieterman, E.J. (author), Princen, H.M.G. (author), Jarke, A. (author), Nilsson, R. (author), Cavallin, A. (author), Bergenholm, L. (author), Henricsson, M. (author), Gopaul, V.S. (author), Agrawal, R. (author), Nissen, S.E. (author), Hurt-Camejo, E. (author)

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 μL/mouse/day for 16 weeks (15 mice/group). Intestinal permeability was increased with mineral versus...

article 2021

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Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs

Gopaul, V.S. (author), Pieterman, E.J. (author), Princen, H.M.G. (author), Bergenholm, L. (author), Lundborg, E. (author), Cavallin, A. (author), Johansson, M.J. (author), Hawthorne, G. (author), Björkbom, A. (author), Hammarberg, M. (author), Li, X. (author), Jarke, A. (author), Bright, J. (author), Svensson, L. (author), Jansson-Löfmark, R. (author), Abrahamsson, B. (author), Agrawal, R. (author), Hurt-Camejo, E. (author)

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho...

article 2021

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Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice

van Gemert, Y. (author), Kozijn, A.E. (author), Pouwer, M.G. (author), Kruisbergen, N.N.L. (author), van den Bosch, M.H.J. (author), Blom, A.B. (author), Pieterman, E.J. (author), Weinans, H. (author), Stoop, R. (author), Princen, H.M.G. (author), van Lent, P.L.E.M. (author)

Objective: High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE*3Leiden.CETP mice. Methods:...

article 2021

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Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice

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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In Vivo Magnetic Resonance Imaging-Based Detection of Heterogeneous Endothelial Response in Thoracic and Abdominal Aorta to Short-Term High-Fat Diet Ascribed to Differences in Perivascular Adipose Tissue in Mice

Bar, A. (author), Kieronska-Rudek, A. (author), Proniewski, B. (author), Suraj-Prazmowska, J. (author), Czamara, K. (author), Marczyk, B. (author), Matyjaszczyk-Gwarda, K. (author), Jasztal, A. (author), Kus, E. (author), Majka, Z. (author), Kaczor, A. (author), Kurpinska, A. (author), Walczak, M. (author), Pieterman, E.J. (author), Princen, H.M.G. (author), Chlopicki, S. (author)

Background Long-term feeding with a high-fat diet (HFD) induces endothelial dysfunction in mice, but early HFD-induced effects on endothelium have not been well characterized. Methods and Results Using an magnetic resonance imaging-based methodology that allows characterization of endothelial function in vivo, we demonstrated that short-term (2...

article 2020

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Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative

Stokman, G. (author), van den Hoek, A.M. (author), Denker Thorbekk, D. (author), Pieterman, E.J. (author), Skovgård Veidal, S. (author), Basta, B. (author), Iruarrizaga-Lejarreta, M. (author), van der Hoorn, J.W. (author), Verschuren, L. (author), Berbée, J.F.P. (author), Rensen, P.C.N. (author), Skjæret, T. (author), Alonso, C. (author), Feigh, M. (author), Kastelein, J.J.P. (author), Friedman, S.L. (author), Princen, H.M.G. (author), Fraser, D.A. (author)

article 2020

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Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice

van den Hoek, A.M. (author), Pieterman, E.J. (author), van der Hoorn, J.W. (author), Iruarrizaga-Lejarreta, M. (author), Alonso, C. (author), Verschuren, L. (author), Skjæret, T. (author), Princen, H.M.G. (author), Fraser, D.A. (author)

Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting and used rodents to evaluate the effects of icosabutate on glucose metabolism, insulin...

article 2020

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Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

Hardtner, C. (author), Kornemann, J. (author), Krebs, K. (author), Ehlert, C.A. (author), Jander, A. (author), Zou, J. (author), Christopher, (author), Starz, C. (author), Rauterberg, S. (author), Sharipova, D. (author), Dufner, B. (author), Hoppe, N. (author), Dederichs, T.S. (author), Willecke, F. (author), Stachon, p. (author), Heidt, T. (author), Wolf, D. (author), von zur Muhlen, C. (author), Madl, J. (author), Kohl, P. (author), Kaeser, R. (author), Boettler, T. (author), Pieterman, E.J. (author), Princen, H.M.G. (author), Ho-Tin-Noe, B. (author), Swirski, F.K. (author), Robbins, C.S. (author), Bode, C. (author), Zirlik, A. (author), Hilgendorf, I. (author)

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte...

article 2020

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The APOE∗3-Leiden Heterozygous Glucokinase Knockout Mouse as Novel Translational Disease Model for Type 2 Diabetes, Dyslipidemia, and Diabetic Atherosclerosis

Pouwer, M.G. (author), Heinonen, S.E. (author), Behrendt, M. (author), Andréasson, A.M. (author), Koppen A. van, (author), Menke, A.L. (author), Pieterman, E.J. (author), van den Hoek, A.M. (author), Jukema, J.W. (author), Leighton, B. (author), Jonsson-Rylander, A.M. (author), Princen, H.M.G. (author)

Background. There is a lack of predictive preclinical animal models combining atherosclerosis and type 2 diabetes. APOE*3-Leiden (E3L) mice are a well-established model for diet-induced hyperlipidemia and atherosclerosis, and glucokinase+/− (GK+/−) mice are a translatable disease model for glucose control in type 2 diabetes. The respective mice...

article 2019

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Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans

van Keulen, D. (author), Pouwer, M.G. (author), Emilsson, V. (author), Matic LP, (author), Pieterman, E.J. (author), Hedin, U. (author), Gudnason, V. (author), Jennings, L.L. (author), Holmstrøm, K. (author), Nielsen, B.S. (author), Pasterkamp, G. (author), Lindeman, J.H.N. (author), van Gool, A.J. (author), Sollewijn Gelpke, M.D. (author), Princen, H.M.G. (author), Tempel, D. (author)

OBJECTIVE: Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. APPROACH AND RESULTS: Gene...

article 2019

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Dose effects of ammonium perfluorooctanoate on Lipoprotein Metabolism in APOE*3-Leiden.CETP mice

Pouwer, M.G. (author), Pieterman, E.J. (author), Chang, S.C. (author), Olsen, G.W. (author), Verschuren, L. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Epidemiological studies have reported positive associations between serum perfluorooctanoic acid (PFOA) and total and non-high-density lipoprotein cholesterol (non-HDL-C) although the magnitude of effect of PFOA on cholesterol lacks consistency. The objectives of this study were to evaluate the effect of PFOA on plasma cholesterol and...

article 2019

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Variable cartilage degradation in mice with diet-induced metabolic dysfunction: Food for thought

Kozijn, A.E. (author), Gierman, L.M. (author), van der Ham, F. (author), Mulder, P. (author), Morrison, M.C. (author), Kühnast, S. (author), van der Heijden, R.A. (author), Stavro, P.M. (author), van Koppen, A. (author), Pieterman, E.J. (author), van den Hoek, A.M. (author), Kleemann, R. (author), Princen, H.M.G. (author), Mastbergen, S.C. (author), Lafeber, F.P.J.G. (author), Zuurmond, A.M. (author), Bobeldijk, I. (author), Weinans, H. (author), Stoop, R. (author)

Objective. Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was...

article 2018

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The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model

Pouwer, M.G. (author), Pieterman, E.J. (author), Verschuren, L. (author), Caspers, M.P.M. (author), Kluft, C. (author), Garcia, R.A. (author), Aman, J. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the vascular adverse effects of three generations of TKIs in a translational model for atherosclerosis, the APOE*3Leiden.CETP mouse. Mice were treated for sixteen...

article 2018

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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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Comment on "Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice" by Rebholz S.L. et al. Toxicol. Rep. 2016 (3) 46-54

Princen, H.M.G. (author), Pouwer, M.G. (author), Pieterman, E.J. (author)

article 2016

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Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

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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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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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