Bone Marrow Ts65Dn Trisomy-Induced Changes in Platelet Functionality and Lymphocytopenia Do Not Impact Atherosclerosis Susceptibility in Mice

Journal of Cardiovascular Development and Disease, vol. 8, pp. 110

Abstract

The genetic disorder Down syndrome is associated with a decreased susceptibility for atherosclerotic cardiovascular disease. Hematological and immune abnormalities occur frequently in Down syndrome patients. We evaluated, in a preclinical setting, the impact of a Down syndrome-like hematological/immune phenotype on atherosclerosis susceptibility. Hereto, hypercholesterolemic low-density lipoprotein receptor knockout mice were transplanted with bone marrow from either a trisomic Ts65Dn mouse or euploid wild-type control and subsequently fed a Western-type diet to induce the development of atherosclerotic lesions. T and B cell concentrations were markedly reduced in blood of Ts65Dn bone marrow recipients (p < 0.001). Expression levels of the pro-atherogenic scavenger receptor CD36 were respectively 37% and 59% lower (p < 0.001) in trisomic monocytes and macrophages. However, these combined effects did not translate into an altered atherosclerosis susceptibility. Notably, blood platelet numbers were elevated in Ts65Dn bone marrow recipients (+57%; p < 0.001), which was paralleled by higher platelet GPVI protein expression (+35%; p < 0.001) and an enhanced collagen-induced platelet activation (p < 0.001). In conclusion, we have shown that providing mice with a Down syndrome-like hematological profile does not change the susceptibility to atherosclerosis. Furthermore, our studies have uncovered a novel effect of the trisomy on platelet functionality that may be relevant in human clinical settings.

Authors 4

1. Suzanne J.A. Korporaal Aachen Division of BioTherapeutics, Leiden Academic Centre for Drug Research Gorlaeus Laboratories

   Leiden University · Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

2. Ronald J. van der Sluis Aachen Division of BioTherapeutics, Leiden Academic Centre for Drug Research Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

3. Miranda Van Eck Aachen Division of BioTherapeutics, Leiden Academic Centre for Drug Research Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

4. Menno Hoekstra corresponding Aachen Division of BioTherapeutics, Leiden Academic Centre for Drug Research Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands