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Training (Stages)


Cardiovascular Research Group



Genetics of human cardiovascular research


Generation and analysis of mouse models



1. Espirito Santo S.M., N.M. Pires, L.S. Boesten, G. Gerritsen, N. Bovenschen , K. Willems van Dijk, J.W. Jukema, H.M. Princen, A. Bensadoun , W.P. Li , J. Herz, L.M. Havekes, and B.J. van Vlijmen. Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. 2004. Blood. 103: 3777-82.

2. Schaap, F.G., P.J. Voshol, P.C.N. Rensen, H.N. van der Vliet, R.A.F.M. Chamuleau, N. Maeda, L.M. Havekes, A.K. Groen and K. Willems van Dijk. 2004. ApoAV expression ameliorates type III hyperlipidemia in mouse models by stimulating lipoprotein lipase-mediated VLDL-triglyceride hydrolysis. J. Biol. Chem. 279:27941-7.

3. Goudriaan J.R., S.M. Espirito Santo, P.J. Voshol, B. Teusink , K. Willems Van Dijk , B.J. van Vlijmen, J.A.Romijn, L.M. Havekes, and P.C. Rensen. 2004. The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis. J Lipid Res. 45:1475-81

4. Willems van Dijk, K., P.C.N. Rensen, P.J. Voshol, and L.M. Havekes. 2004.The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism? Cur.Opin. Lipidol.15:239-46.


5. Bovenschen N, Willems van Dijk K, Havekes LM, Mertens K, van Vlijmen BJ. Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice. Br J Haematol. 2004. 126:722-5.




1. Gerritsen, G., K.E. Kypreos, A. van der Zee, B. Teusink, V.I. Zannis, L.M. Havekes, K. Willems van Dijk. 2003. Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain. J. Lipid Res. 44: 408

2. Kypreos, K.E., X. Li, K. Willems van Dijk, L.M. Havekes, V.I. Zannis. 2003. Molecular mechanisms of type III hyperlipoproteinemia: the contribution of the carboxy-terminal domain of apoE can account for the dyslipidemia that is associated with the E2/E2 phenotype. Biochemistry. 42: 9841.


3. Willems van Dijk, K., K.E. Kypreos, C. d’Oliveira, F. Fallaux. 2003. Adenovirus mediated gene transfer. M. Hofker and J van Deursen (Eds). Transgenic mouse methods and protocols. Methods Mol. Biol. 209: 231


1.Tacken, P.J., D.J.M. Delsing, M.J.J. Gijbels, P.H.A. Quax, L.M. Havekes, M.H. Hofker, K. Willems van Dijk. 2002. VLDL receptor deficiency enhances intimal thickening after vascular injury but does not affect atherosclerotic lesion area. Atherosclerosis. 162: 103


1. Van Eck, M., K. Willems van Dijk, N. Herijgers, M.H. Hofker, P.H. Groot, T.J. van Berkel. 2001. Essential role for the (hepatic) LDL receptor in macrophage apolipoprotein E-induced reduction in serum cholesterol levels and atherosclerosis. Atherosclerosis. 154:103


2. Kypreos*, K.E., K. Willems van Dijk*, A. van der Zee, L.M. Havekes, V.I. Zannis. 2001. Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo: the carboxylterminal region 203-299 promotes hepatic VLDL-triglyceride secretion. J. Biol. Chem. 276: 19778 *Shared first authorship.


3. Jaari S., K. Willems van Dijk, V.M. Olkkonen, A. van der Zee, J. Metso, L. Havekes, M. Jauhiainen, C. Ehnholm. 2001. Dynamic changes in mouse lipoproteins induced by transiently expressed human phospholipid transfer protein (PLTP): importance of PLTP in prebeta-HDL generation. Comp. Biochem. Physiol. B. Biochem. Mol. Biol.128:781.


4. Tacken, P.J., A. van der Zee, T.L. Beumer, R.L. Florijn, M.J.J. Gijbels, L.M. Havekes, R.R. Frants, K. Willems van Dijk, M.H. Hofker. 2001. Effective generation of low density lipoprotein receptor transgenic mice by overlapping genomic DNA fragments: high testis expression and disturbed spermatogenesis. Transgenic Res. 10:211

5. Tacken, P.J., M.H. Hofker, L.M. Havekes, K. Willems van Dijk. Living up to a name: the role of the VLDL receptor in lipid metabolism. 2001. Curr. Opin. Lipidol. 12:275.

6. Kypreos, K.E., B. teusink, K. Willems van Dijk, L.M. Havekes, V.I. Zannis. 2001. Analysis of the structure and function relationship of the human apolipoprotein E in vivo, using adenovirus-mediated gene transfer. FASEB J. Express article: 10.1096/fj.00-0882fje, printed version: FASEB J. 2001 15:1598

7. Kypreos, K.E., P. Morani, K. Willems van Dijk, L.M. Havekes, V.I. Zannis. The aminoterminal 1-185 domain of apoE promotes the clearance of lipoprotein remnants in vivo. The carboxyterminal domain is required for induction of hyperlipidemia in normal and apoE-deficient mice. 2001. Biochemistry. 40:6027

8. Mensenkamp A.R., B. Teusink, J.F. Baller, H. Wolters, R. Havinga, K. Willems van Dijk, L.M. Havekes, F. Kuipers. 2001. Mice expressing only the mutant apoe3leiden gene show impaired vldl secretion. Arterioscler. Thromb. Vasc. Biol. 21:1366

9. Goudriaan, J.R., P.J. Tacken, V.E.H. Dahlmans, M.J.J. Gijbels, K. Willems van Dijk, L.M. Havekes, M.C. Jong. 2001. Protection from obesity in mice lacking the VLDL receptor. Arterioscler. Thromb. Vasc. Biol. 21:1488

10. Teusink b., A.R. Mensenkamp, H. van der Boom, F. Kuipers, K. Willems van Dijk, and L.M. Havekes Stimulation of the in vivo production of very low density lipoproteins by apolipoprotein E is independent of the presence of the LDL receptor. 2001. J. Biol. Chem. 276: 40693


1. Willems Van Dijk K, Hofker MH, Havekes LM. Use of transgenic mice to study the role of apolipoprotein E in lipid metabolism and atherosclerosis. Int J Tissue React 2000;22(2-3):49-58.

2. van Eck M, Herijgers N, Willems van Dijk K, Havekes LM, Hofker MH, Groot PH, Van Berkel TJ. Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg158-->Cys) on cholesterol levels and atherosclerosis in ApoE- deficient mice. Arterioscler Thromb Vasc Biol 2000;20(1):119-27.

3. Tacken PJ, Beer FD, Vark LC, Havekes LM, Hofker MH, Willems Van Dijk K. Very-low-density lipoprotein binding to the apolipoprotein E receptor 2 is enhanced by lipoprotein lipase, and does not require apolipoprotein E. Biochem J 2000;347(Pt 2):357-361.

4. de Winther MP, Gijbels MJ, Willems van Dijk K, Havekes LM, Hofker MH. Transgenic mouse models to study the role of the macrophage scavenger receptor class A in atherosclerosis. Int J Tissue React 2000;22(2-3):85-91.

5. de Winther MP, van Dijk KW, Havekes LM, Hofker MH. Macrophage scavenger receptor class A : A multifunctional receptor in atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20(2):290-7.

6. de Beer, F., K. Willems van Dijk, M.C. Jong, L.C. van Vark, A. van Der Zee, M.H. Hofker, F.J. Fallaux, R.C. Hoeben, A.H. Smelt, L.M. Havekes. 2000. Apolipoprotein E2 (Lys146-->Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides. Arterioscler. Thromb. Vasc. Biol. 20:1800

7. Tacken, P.J., B. Teusink, M. C. Jong, D. Harats, L. M. Havekes, K. Willems van Dijk, M. H. Hofker. 2000. LDL receptor deficiency unmasks altered VLDL triglyceride metabolism in VLDL receptor transgenic and knockout mice. J. Lipid Res. 41:2055


1. Willems van Dijk K, Hofker MH, Havekes LM. Dissection of the complex role of apolipoprotein E in lipoprotein metabolism and atheosclerosis using mouse models. Current Atherosclerosis Reports 1999;1(2):101-107.

2. Willems van Dijk K, van Vlijmen BJM, de Winther MPJ, van 't Hof B, van der Zee A, van der Boom H, Havekes LM, Hofker MH. Hyperlipidemia of APOE2(arg158-cys) and APOE3-Leiden transgenic mice is modulated predominantly by low density lipoprotein receptor expression. Arterioscler. Thromb. Vasc . Biol. 1999;19:2945-2951.

3. Willems van Dijk K, van Vlijmen BJ, van't Hof HB, van der Zee A, Santamarina-Fojo S, van Berkel TJ, Havekes LM, Hofker MH. In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE. J Lipid Res 1999;40(2):336-344.

4. Mensenkamp AR, Jong MC, van Goor H, van Luyn MJ, Bloks V, Havinga R, Voshol PJ, Hofker MH, van Dijk KW, Havekes LM and others. Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver. J Biol Chem 1999;274(50):35711-8.

5. Jong MC, Willems van Dijk K, Dahlmans VE, Van der Boom H, Kobayashi K, Oka K, Siest G, Chan L, Hofker MH, Havekes LM. Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor. Biochem J 1999;338(Pt 2):281-7.

6. de Winther MPJ, Willems van Dijk K, van Vlijmen BJM, Gijbels MJJ, Heus JJ, Wijers ER, van den Bos AC, Breuer M, Frants RR, Havekes LM and others. 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. Atherosclerosis 1999;147:339

7. de Winther MP, Gijbels MJ, van Dijk KW, van Gorp PJ, suzuki H, Kodama T, Frants RR, Havekes LM, Hofker MH. Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice. Atherosclerosis 1999;144(2):315-21.

8. de Beer F, Hendriks WL, van Vark LC, Kamerling SW, Willems van Dijk K, Hofker MH, Smelt AH, Havekes LM. Binding of beta-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas ApoE only modulates binding affinity. Arterioscler Thromb Vasc Biol 1999;19(3):633-7.


1. Willems van Dijk K, van Vlijmen BJ, van der Zee A, van't Hof B, van der Boom H, Kobayashi K, Chan L, Havekes LM, Hofker MH. Reversal of hypercholesterolemia in apolipoprotein E2 and apolipoprotein E3-Leiden transgenic mice by adenovirus-mediated gene transfer of the VLDL receptor. Arterioscler Thromb Vasc Biol 1998;18(1):7-12.

2. Ehnholm S, Willems van Dijk K, van 't Hof B, van der Zee A, Olkkonen VM, Jauhiainen M, Hofker M, Havekes L, Ehnholm C. Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice. J Lipid Res 1998;39(6):1248-53.


1. Havekes LM, van Vlijmen BJ, Jong MC, Willems van Dijk K, Hofker MH. Use of transgenic mice in lipoprotein metabolism and atherosclerosis research. Prostaglandins Leukot Essent Fatty Acids 1997;57(4-5):463-6.

2. van Vlijmen BJ, Willems van Dijk K, van't Hof HB, van Gorp PJ, van der Zee A, van der Boom H, Breuer ML, Hofker MH, Havekes LM. In the absence of endogenous mouse apolipoprotein E, apolipoprotein E*2(Arg-158 --> Cys) transgenic mice develop more severe hyperlipoproteinemia than apolipoprotein E*3-Leiden transgenic mice. J.Biol.Chem. 1996;271(48):30595-30602.

3. Jong MC, Dahlmans VE, van Gorp PJ, Willems van Dijk K, Breuer ML, Hofker MH, Havekes LM. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoprotein via a receptor-associated protein-sensitive pathway. J.Clin.Invest. 1996;98:2259-2267.


Novel gene discovery using mouse models




1. Kreeft AJ, Moen CJ, Hofker MH, Frants RR, Vreugdenhil E, Gijbels MJ, Havekes LM, Datson NA. Identification of differentially regulated genes in mildly hyperlipidemic ApoE3-Leiden mice by use of serial analysis of gene expression. Arterioscler Thromb Vasc Biol. 2001 21:1984-90.


2. Svensson BA, Kreeft AJ, van Ommen GJ, den Dunnen JT, Boer JM. GeneHopper: a web-based search engine to link gene-expression platforms through GenBank accession numbers. Genome Biol. 2003 4(5):R35