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No effects of PCSK9-inhibitor treatment on spatial learning, locomotor activity, and novel object recognition in mice

Schlunk, F. (author), Fisher, P. (author), Princen, H.M.G. (author), Rex, A. (author), Prinz, V. (author), Foddis, M. (author), Lütjohann, D. (author), Laufs, U. (author), Endres, M. (author)

Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PSCK9) neutralizing antibodies effectively lower plasma cholesterol levels and decrease cardiovascular events but also raised some concern that cognitive function could worsen as a side effect. Here, we performed experiments in mice to characterize the effect of anti-PCSK9 antibodies...

article 2021

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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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Efficacy, safety and novel targets in cardiovascular disease: advanced applications in APOE*3-Leiden.CETP mice

Pouwer, M.G. (author)

The thesis discussed several strategies that may contribute to further CVD risk reduction in the future. We described two novel lipid-lowering strategies, we unraveled (part of) the etiology of the cardiovascular safety issues of TKIs that are used for the treatment of CML, and we investigated the dose effects of PFOA on lipoprotein metabolism....

doctoral thesis 2020

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Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Ruiz-Zapata, A.M. (author), Heinz, A. (author), Kerkhof, M.H. (author), van de Westerlo-van Rijt, C. (author), Schmelzer, C.E.H. (author), Stoop, R. (author), Kluivers, K.B. (author), Oosterwijk, E. (author)

Fibroblast to myofibroblast differentiation is a key feature of wound-healing in soft tissues, including the vagina. Vaginal fibroblasts maintain the integrity of the vaginal wall tissues, essential to keep pelvic organs in place and avoid pelvic organ prolapse (POP). The micro-environment of vaginal tissues in POP patients is stiffer and has...

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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Biochemical Characterization of Mouse Retina of an Alzheimer's Disease Model by Raman Spectroscopy

Stiebing, C. (author), Jahn, I.J. (author), Schmitt, M. (author), Keijzer, N. (author), Kleemann, R. (author), Kiliaan, A.J. (author), Drexler, W. (author), Leitgeb, R.A. (author), Popp, J. (author)

The presence of biomarkers characteristic for Alzheimer's disease in the retina is a controversial topic. Raman spectroscopy offers information on the biochemical composition of tissues. Thus, it could give valuable insight into the diagnostic value of retinal analysis. Within the present study, retinas of a double transgenic mouse model, that...

article 2020

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Osteoarthritis: at the crossroads of metabolism and inflammation [Artrose: op het snijvlak van metabolisme en ontsteking]

Kozijn, A.E. (author)

This thesis aimed to investigate how metabolic overload contributes to the pathophysiology of knee OA. We explored the role of these independent yet intertwined processes using state-of-the-art lipidomic and cellular approaches in mouse models of diet-induced OA. Chapter 2 presents an overview of twelve preclinical studies in which mice received...

doctoral thesis 2020

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A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

van den Hoek, A.M. (author), Verschuren, L. (author), Worms, N. (author), van Nieuwkoop, A. (author), de Ruiter, C. (author), Attema, J. (author), Menke, A.L. (author), Caspers, M.P.M. (author), Radhakrishnan, S. (author), Salic, K. (author), Kleemann, R. (author)

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr−/−. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr−/−....

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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Effects of Inhibition or Deletion of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) on Intracerebral Hemorrhage Volumes in Mice

Schlunk, F. (author), Fisher, P. (author), Princen, H.M.G. (author), Rex, A. (author), Prinz, V. (author), Foddis, M. (author), Lütjohann, D. (author), Laufs, U. (author), Endres, M. (author)

Anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) antibodies lower low-density lipoprotein cholesterol levels and significantly reduce cardiovascular end points.1 Safety concerns were raised as ultra-low levels of low-density lipoprotein cholesterol can be achieved. Low cholesterol levels are associated with an increased rate of...

article 2020

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Diffusion of charged and uncharged contrast agents in equine mandibular condylar cartilage is not affected by an increased level of sugar-induced collagen crosslinking

Mirahmadi, F. (author), Koolstra, J.H. (author), Fazaeli, S. (author), Lobbezoo, F. (author), van Lenthe, G.H. (author), Snabel, J. (author), Stoop, R. (author), Everts, V. (author)

Nutrition of articular cartilage relies mainly on diffusion and convection of solutes through the interstitial fluid due to the lack of blood vessels. The diffusion is controlled by two factors: steric hindrance and electrostatic interactions between the solutes and the matrix components. Aging comes with changes in the cartilage structure and...

article 2019

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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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FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice

Yakala, G.K. (author), Cabrera-Fuentes, H.A. (author), Crespo-Avilan, G.E. (author), Rattanasopa, C. (author), Burlacu, A. (author), George, B.L. (author), Anand, K. (author), Mayan, D.C. (author), Corliano, M. (author), Hernandez-Resendiz, S. (author), Wu, Z. (author), Schwerk, A.M.K. (author), Tan, A.L.J. (author), Trigueros-Motos, L. (author), Chevre, R. (author), Chua, T. (author), Kleemann, R. (author), Liehn, E.A. (author), Hausenloy, D.J. (author), Ghosh, S. (author), Singaraja, R.R. (author)

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member...

article 2019

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Anti-PCSK9 antibodies inhibit pro-atherogenic mechanisms in APOE*3Leiden.CETP mice

Schuster, S. (author), Rubil, S. (author), Endres, M. (author), Princen, H.M.G. (author), Boeckel, J.N. (author), Winter, K. (author), Werner, C. (author), Laufs, U. (author)

LDL-cholesterol (LDL-C) is a causal pathogenic factor in atherosclerosis. Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralizing antibodies are novel potent LDL-lowering drugs which reduce cardiovascular events. To characterize their effect on atherogenesis, APOE*3Leiden.CETP mice were fed a high cholesterol/high fat...

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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Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet

Kozijn, A.E. (author), Tartjiono, M.T. (author), Ravipati, S. (author), van der Ham, F. (author), Barrett, D.A. (author), Mastbergen, S.C. (author), Korthagen, N.M. (author), Lafeber, F.P.J.G. (author), Zuurmond, A.M. (author), Bobeldijk, I. (author), Weinans, H. (author), Stoop, R. (author)

Objective. C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP ...

article 2019