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Macrophage p53 controls macrophage death in atherosclerotic lesions of apolipoprotein E deficient mice

Boesten, L.S.M. (author), Zadelaar, A.S.M. (author), van Nieuwkoop, A. (author), Hu, L. (author), Teunisse, A.F.A.S. (author), Jochemsen, A.G. (author), Evers, B. (author), van de Water, B. (author), Gijbels, M.J.J. (author), van Vlijmen, B.J.M. (author), Havekes, L.M. (author), de Winther, M.P.J. (author), TNO Kwaliteit van Leven (author)

The cellular composition of atherosclerotic lesions is determined by many factors including cell infiltration, proliferation and cell death. Tumor suppressor gene p53 has been shown to regulate both cell proliferation and cell death in many cell types. In the present study, we investigated the role of macrophage p53 in the pathogenesis of early...

article 2009

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The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI

TNO Kwaliteit van Leven (author), Hu, L. (author), van der Hoogt, C.C. (author), Espirito Santo, S.M.S. (author), Out, R. (author), Kypreos, K.E. (author), van Vlijmen, B.J.M. (author), van Berkel, T.J.C. (author), Romijn, J.A. (author), Havekes, L.M. (author), van Dijk, K.W. (author), Rensen, P.C.N. (author)

LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance...

article 2008

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Plasma plasminogen activator inhibitor-1 level is not regulated by the hepatic low-density lipoprotein receptor-related protein [2]

Hu, L. (author), Bovenschen, N. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Tamsma, J.T. (author), TNO Kwaliteit van Leven (author)

article 2007

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The influence of established genetic variation in the haemostatic system on clinical restenosis after percutaneous coronary interventions

TNO Kwaliteit van Leven (author), Pons, D. (author), Monraats, P.S. (author), de Maat, M.P.M. (author), Pires, N.M.M. (author), Quax, P.H.A. (author), van Vlijmen, B.J.M. (author), Rosendaal, F.R. (author), Zwinderman, A.H. (author), Doevendans, P.A.F.M. (author), Waltenberger, J. (author), de Winter, R.J. (author), Tio, R.A. (author), Frants, R.R. (author), van der Laarse, A. (author), van der Wall, E.E. (author), Jukema, J.W. (author)

Since activation of the haemostatic system is an important feature of the wound healing response triggered by arterial injury, variations in genes involved in thrombus formation may play a role in restenosis after percutaneous coronary interventions (PCI). Therefore, our aim was to examine the relationship between polymorphisms that are known to...

article 2007

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Local cre-mediated gene recombination in vascular smooth muscle cells in mice

Zadelaar, A.S.M. (author), Boesten, L.S.M. (author), Pires, N.M.M. (author), van Nieuwkoop, A. (author), Biessen, E.A.L. (author), Jukema, W. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), van Dijk, K.W. (author), TNO Kwaliteit van Leven (author)

Here we describe a means to conditionally modify genes at a predefined and localized region of the vasculature using a perivascular drug delivery device (PDD). A 4-hydroxytamoxifen (4-OHT)-eluting PDD was applied around the carotid or femoral artery of a mouse strain carrying both the tamoxifen-inducible and smooth muscle cell (SMC)-specific Cre...

article 2006

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Dual PPARα/γ agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice

Zadelaar, A.S.M. (author), Boesten, L.S.M. (author), Jukema, J.W. (author), van Vlijmen, B.J.M. (author), Kooistra, T. (author), Emeis, J.J. (author), Lundholm, E. (author), Camejo, G. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

OBJECTIVE - We investigated whether the dual PPARα/γ agonist tesaglitazar has anti-atherogenic effects in ApoE*3Leiden mice with reduced insulin sensitivity. METHODS AND RESULTS - ApoE*3Leiden transgenic mice were fed a high-fat (HF) insulin-resistance-inducing diet. One group received a high-cholesterol (HC) supplement (1% wt/wt; HC group). A...

article 2006

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Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in apoE/LDLR double knockout mice

Hu, L. (author), Boesten, L.S.M. (author), May, P. (author), Herz, J. (author), Bovenschen, N. (author), Huisman, M.V. (author), Berbée, J.F.P. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Tamsma, J.T. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins. METHODS AND RESULTS - We generated...

article 2006

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Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice

Boesten, L.S.M. (author), Zadelaar, A.S.M. (author), van Nieuwkoop, A. (author), Hu, L. (author), Jonkers, J. (author), van de Water, B. (author), Gijbels, M.J.J. (author), van der Made, I. (author), de Winther, M.P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), TNO Kwaliteit van Leven (author)

The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE...

article 2006

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Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

TNO Kwaliteit van Leven (author), Boesten, L.S.M. (author), Zadelaar, A.S.M. (author), de Clercq, S. (author), Francoz, S. (author), van Nieuwkoop, A. (author), Biessen, E.A.L. (author), Hofmann, F. (author), Feil, S. (author), Feil, R. (author), Jochemsen, A.G. (author), Zurcher, C. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Marine, J.C. (author)

p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle...

article 2006

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Genetic inflammatory factors predict restenosis after percutaneous coronary interventions

Monraats, P.S. (author), Pires, N.M.M. (author), Agema, W.R.P. (author), Zwinderman, A.H. (author), Schepers, A. (author), de Maat, M.P.M. (author), Doevendans, P.A. (author), de Winter, R.J. (author), Tio, R.A. (author), Waltenberger, J. (author), Frants, R.R. (author), Quax, P.H.A. (author), van Vlijmen, B.J.M. (author), Atsma, D.E. (author), van der Laarse, A. (author), van der Wall, E.E. (author), Jukema, J.W. (author), TNO Kwaliteit van Leven (author)

Background - Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have...

article 2005

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Tumor necrosis factor-α plays an important role in restenosis development

Monraats, P.S. (author), Pires, N.M.M. (author), Schepers, A. (author), Agema, W.R.P. (author), Boesten, L.S.M. (author), de Vries, M.R. (author), Zwinderman, A.H. (author), de Maat, M.P.M. (author), Doevendans, P.A.F.M. (author), de Winter, R.J. (author), Tio, R.A. (author), Waltenberger, J. (author), 't Hart, L.M. (author), Frants, R.R. (author), Quax, P.H.A. (author), van Vlijmen, B.J.M. (author), Havekes, L.M. (author), van der Laarse, A. (author), van der Wall, E.E. (author), Jukema, J.W. (author), TNO Kwaliteit van Leven (author)

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFα, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER)...

article 2005

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Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

TNO Kwaliteit van Leven (author), Espirito Santo, S.M.S. (author), Rensen, P.C.N. (author), Goudriaan, J.R. (author), Bensadoun, A. (author), Bovenschen, N. (author), Voshol, P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author)

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the...

article 2005

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Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice

Bovenschen, N. (author), van Dijk, K.W. (author), Havekes, L.M. (author), Mertens, K. (author), van Vlijmen, B.J.M. (author), Gaubius Instituut TNO (author)

Low-density lipoprotein receptor-related protein (LRP) contributes to factor VIII (FVIII) catabolism in vivo. Besides LRP, FVIII also interacts with very low-density lipoprotein receptor (VLDLR) in vitro. We investigated the physiological role of VLDLR in FVIII catabolism, using knockout mouse models for VLDLR and LRP, alone and in combination....

article 2004

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Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Espirito Santo, S.M.S. (author), Pires, N.M.M. (author), Boesten, L.S.M. (author), Gerritsen, G. (author), Bovenschen, N. (author), van Dijk, K.W. (author), Jukema, J.W. (author), Princen, H.M.G. (author), Bensadoun, A. (author), Li, W.P. (author), Herz, J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Gaubius Instituut TNO (author)

The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis...

article 2004

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The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis

Gaubius Instituut TNO (author), Goudriaan, J.R. (author), Espirito Santo, S.M.S. (author), Voshol, P.J. (author), Teusink, B. (author), van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)

The VLDL receptor (VLDLr) is involved in tissue delivery of VLDL-triglyceride (TG)-derived FFA by facilitating the expression of lipoprotein lipase (LPL). However, vldlr-/- mice do not show altered plasma lipoprotein levels, despite reduced LPL expression. Because LPL activity is crucial in postprandial lipid metabolism, we investigated whether...

article 2004

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Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53

von der Thüsen, J.H. (author), van Vlijmen, B.J.M. (author), Hoeben, R.C. (author), Kockx, M.M. (author), Havekes, L.M. (author), van Berkel, T.J.C. (author), Biessen, E.A.L. (author)

Background - The presence of the tumor-suppressor gene p53 in advanced atherosclerotic plaques and the sensitivity to p53-induced cell death of smooth muscle cells isolated from these plaques have fueled speculation about the role of p53 in lesion destabilization and plaque rupture. In this study, we describe a strategy to promote (thrombotic)...

article 2002

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Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice

van Vlijmen, B.J.M. (author), Gerritsen, G. (author), Franken, A.L. (author), Boesten, L.S.M. (author), Kockx, M.M. (author), Gijbels, M.J. (author), Vierboom, M.P. (author), van Eck, M. (author), van de Water, B. (author), van Berkel, T.J.C. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

Cell proliferation and cell death (either necrosis or apoptosis) are key processes in the progression of atherosclerosis. The tumor suppressor gene p53 is an essential gene in cell proliferation and cell death and is upregulated in human atherosclerotic plaques, both in smooth muscle cells and in macrophages. In the present study, we...

article 2001

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Hyperlipidemia of ApoE2(Arg158-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression

van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), de Winther, M.P.J. (author), van 't Hof, B. (author), van der Zee, A. (author), van der Boom, H. (author), Havekes, L.M. (author), Hofker, M.H. (author), Gaubius instituut TNO (author)

To investigate the relative roles of the LDL receptor- and non-LDL receptor-mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg158-Cys) (apoE2) and apoE3- Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-...

article 1999

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Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages

de Winther, M.P.J. (author), van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), Gijbels, M.J.J. (author), Heus, J.J. (author), Wijers, E.R. (author), van den Bos, A.C. (author), Breuer, M. (author), Frants, R.R. (author), Havekes, L.M. (author), Hofker, M.H. (author), Gaubius instituut TNO (author)

Macrophage scavenger receptors class A (MSR) are thought to play an important role in atherogenesis by mediating the unrestricted uptake of modified lipoproteins by macrophages in the vessel wall leading to foam cell formation. To investigate the in vivo role of the MSR in this process, a transgenic mouse model expressing both isoforms of the...

article 1999

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An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins

Gaubius instituut TNO (author), van Vlijmen, B.J.M. (author), Rohlmann, A. (author), Page, S.T. (author), Bensadoun, A. (author), Bos, I.S.T. (author), van Berkel, T.J.C. (author), Havekes, L.M. (author), Herz, J. (author)

We have used adenovirus-mediated gene transfer in mice to investigate low density lipoprotein receptor (LDLR) and LDLR-related protein (LRP)- independent mechanisms that control the metabolism of chylomicron and very low density lipoprotein (VLDL) remnants in vivo. Overexpression of receptor- associated protein (RAP) in mice that lack both LRP...

article 1999