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Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice

Mulder, P. (author), Morrison, M.C. (author), Verschuren, L. (author), Liang, W. (author), van Bockel, J.H. (author), Kooistra, T. (author), Wielinga, P.Y. (author), Kleemann, R. (author)

Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD...

article 2016

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A Clinical Evaluation of Statin Pleiotropy: Statins Selectively and Dose-Dependently Reduce Vascular Inflammation

van der Meij, E. (author), Koning, G.G. (author), Vriens, P.W. (author), Peeters, M.F. (author), Meijer, C.A. (author), Kortekaas, K.E. (author), Dalman, R.L. (author), van Bockel, J.H. (author), Hanemaaijer, R. (author), Kooistra, T. (author), Kleemann, R. (author), Lindeman, J.H.N. (author)

Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not...

article 2013

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In vivo suppression of vein graft disease by nonviral, electroporation-mediated, gene transfer of tissue inhibitor of metalloproteinase-1 linked to the amino terminal fragment of urokinase (TIMP-1.ATF), a cell-surface directed matrix metalloproteinase inhibitor

Eefting, D. (author), de Vries, M.R. (author), Grimbergen, J.M. (author), Karper, J.C. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Background: Smooth muscle cell (SMC) migration and proliferation are important in the development of intimal hyperplasia, the major cause of vein graft failure. Proteases of the plasminogen activator (PA) system and of the matrix metalloproteinase (MMP) system are pivotal in extracellular matrix degradation and, by that, SMC migration....

article 2010

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A novel urokinase receptor-targeted inhibitor for plasmin and matrix metalloproteinases suppresses vein graft disease

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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The pathophysiology of abdominal aortic aneurysm growth: Corresponding and discordant inflammatory and proteolytic processes in abdominal aortic and popliteal artery aneurysms

Abdul-Hussien, H. (author), Hanemaaijer, R. (author), Kleemann, R. (author), Verhaaren, B.F.J. (author), van Bockel, J.H. (author), Lindeman, J.H.N. (author), TNO Kwaliteit van Leven (author)

Objective: There is remarkable controversy over the processes driving abdominal aneurysm growth. The inherent limitations of animal and human studies hamper elucidation of the key inflammatory and proteolytic processes. Human data are largely derived from surgical specimens that typically reflect the final stages of the disease process and thus...

article 2010

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Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice

Eefting, D. (author), Bot, I. (author), de Vries, M.R. (author), Schepers, A. (author), van Bockel, J.H. (author), van Berkel, T.J.C. (author), Biessen, E.A.L. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Objective: Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the...

article 2009

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Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content

Abdul-Hussien, H. (author), Hanemaaijer, R. (author), Verheijen, J.H. (author), van Bockel, J.H. (author), Geelkerken, R.H. (author), Lindeman, J.H.N. (author), TNO Kwaliteit van Leven (author)

Background: Matrix metalloproteinase-9 (MMP-9) is thought to play a central role in abdominal aortic aneurysm (AAA) initiation. Doxycycline, a tetracycline analogue, has direct MMP-9-inhibiting properties in vitro, and it effectively suppresses AAA development in rodents. Observed inhibition of AAA progression, and contradictory findings in...

article 2009

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MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease

TNO Kwaliteit van Leven (author), Verschuren, L. (author), Kooistra, T. (author), Bernhagen, J. (author), Voshol, P. (author), Ouwens, D.M. (author), van Erk, M. (author), de Vries-van der Weij, J. (author), Leng, L. (author), van Bockel, J.H. (author), Willems van Dijkl, K. (author), Fingerle-Rowson, G. (author), Bucala, R. (author), Kleemann, R. (author)

Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type 2 diabetes. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the...

article 2009

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Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm doxycycline selectively depletes aortic wall neutrophils and cytotoxic t cells

TNO Kwaliteit van Leven (author), Lindeman, J.H.N. (author), Abdul-Hussien, H. (author), van Bockel, J.H. (author), Wolterbeek, R. (author), Kleemann, R. (author)

Background-Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a inical trial and found...

article 2009

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Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm

Lindeman, J.H.N. (author), Abdul-Hussien, H. (author), Schaapherder, A.F.M. (author), van Bockel, J.H. (author), von der Thüsen, J.H. (author), Roelen, D.L. (author), Kleemann, R. (author)

Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription...

article 2008

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Vascular Growth in Ischemic Limbs: A Review of Mechanisms and Possible Therapeutic Stimulation

van Weel, V. (author), van Tongeren, R.B. (author), van Hinsbergh, V.W.M. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Stimulation of vascular growth to treat limb ischemia is promising, and early results obtained from uncontrolled clinical trials using angiogenic agents, e.g., vascular endothelial growth factor, led to high expectations. However, negative results from recent placebo-controlled trials warrant further research. Here, current insights into...

article 2008

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Natural killer cells and CD4+ T-cells modulate collateral artery development

van Weel, V. (author), Toes, R.E.M. (author), Seghers, L. (author), Deckers, M.M.L. (author), de Vries, M.R. (author), Eilers, P.H. (author), Sipkens, J. (author), Schepers, A. (author), Eefting, D. (author), van Hinsbergh, V.W.M. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia. METHODS AND RESULTS - Lymphocytes, detected with markers for NK1.1,...

article 2007

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Expression of vascular endothelial growth factor, stromal cell-derived factor-1, and CXCR4 in human limb muscle with acute and chronic ischemia

van Weel, V. (author), Seghers, L. (author), de Vries, M.R. (author), Kuiper, E.J. (author), Schlingemann, R.O. (author), Bajema, I.M. (author), Lindeman, J.H.N. (author), van Delis-Diemen, P.M. (author), van Hinsbergh, V.W.M. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - Vascular endothelial growth factor (VEGF)-induced stromal cell-derived factor-1 (SDF-1) has been implicated in angiogenesis in ischemic tissues by recruitment of CXCR4-positive bone marrow-derived circulating cells with paracrine functions in preclinical models. Here, evidence for this is provided in patients with peripheral artery...

article 2007

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The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice

Eefting, D. (author), Schepers, A. (author), de Vries, M.R. (author), Pires, N.M.M. (author), Grimbergen, J.M. (author), Lagerweij, T. (author), Nagelkerken, L.M. (author), Monraats, P.S. (author), Jukema, J.W. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Objective: Inflammatory factors are thought to play a regulatory role in restenosis. Interleukin-10 (IL10) is an important anti-inflammatory cytokine with anti-atherogenic potentials. The aim of this study was to assess the effects of IL10 modulation on cuff-induced neointima formation in hypercholesterolemic APOE*3-Leiden mice. Methods: The...

article 2007

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Prolonged in vivo gene silencing by electroporation-mediated plasmid delivery of small interfering RNA

Eefting, D. (author), Grimbergen, J.M. (author), de Vries, M.R. (author), van Weel, V. (author), Kaijzel, E.L. (author), Que, I. (author), Moon, R.T. (author), Löwik, C.W. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

For the successful application of RNA interference in vivo, it is desired to achieve (local) delivery of small interfering RNAs (siRNAs) and long-term gene silencing. Nonviral electrodelivery is suitable to obtain local and prolonged expression of transgenes. By intramuscular electrodelivery of a plasmid in which two opposing human polymerase...

article 2007

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Inhibition of complement component C3 reduces vein graft atherosclerosis in apolipoprotein E3-Leiden transgenic mice

Schepers, A. (author), de Vries, M.R. (author), van Leuven, C.J. (author), Grimbergen, J.M. (author), Holers, V.M. (author), Daha, M.R. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

BACKGROUND - Venous bypass grafts may fail because of development of intimal hyperplasia and accelerated atherosclerosis. Inflammation plays a major role in these processes. Complement is an important part of the immune system and participates in the regulation of inflammation. The exact role of complement in the process of accelerated...

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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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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Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo

van Weel, V. (author), Deckers, M.M.L. (author), Grimbergen, J.M. (author), van Leuven, K.J.M. (author), Lardenoye, J.W.H.P. (author), Schlingemann, R.O. (author), van Nieuw Amerongen, G.P. (author), van Bockel, J.H. (author), van Hinsbergh, V.W.M. (author), Quax, P.H.A. (author), Gaubius Instituut TNO (author)

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography...

article 2004

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Ingrowth of aorta wall into stent grafts impregnated with basic fibroblast growth factor: A porcine in vivo study of blood vessel prosthesis healing

van der Bas, J.M.A. (author), Quax, P.H.A. (author), van den Berg, A.C. (author), Visser, M.J.T. (author), van der Linden, E. (author), van Bockel, J.H. (author), TNO Preventie en Gezondheid (author)

Objective: Endovascular aneurysm repair is an alternative treatment of abdominal aortic aneurysm. The procedure is less invasive, and morbidity and most probably mortality are reduced. However, some problems, such as endoleakage, are yet to be resolved. Endoleakage can occur after graft migration, as a result of insufficient fixation of the...

article 2004