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.
Highlights
The high frequency genetic disorder Down syndrome is associated with a relatively low susceptibility for the development of atherosclerotic cardiovascular disease, characterized by a narrowing of the vessel lumen due to subendothelial accumulation of cholesterol within macrophages
The atherosclerosis resistance phenotype was validated by Ylä-Herttuala et al who detected significantly reduced cholesterol and calcium levels within coronary arteries of institutionalized Down syndrome carriers as compared to both institutionalized subjects suffering from non-Down syndrome-related mental handicaps and non-institutionalized control subjects without mental defects [2]
The relative atherosclerosis resistance of Down syndrome carriers does not seem to be related to an effect of the genetic disorder in the hyperlipidemia extent [3,4]
Summary
The high frequency genetic disorder Down syndrome (trisomy 21; global incidence:1 in 800 births) is associated with a relatively low susceptibility for the development of atherosclerotic cardiovascular disease, characterized by a narrowing of the vessel lumen due to subendothelial accumulation of cholesterol within macrophages. The atherosclerosis resistance phenotype was validated by Ylä-Herttuala et al who detected significantly reduced cholesterol and calcium levels within coronary arteries of institutionalized Down syndrome carriers as compared to both institutionalized subjects suffering from non-Down syndrome-related mental handicaps and non-institutionalized control subjects without mental defects [2]. The relative atherosclerosis resistance of Down syndrome carriers does not seem to be related to an effect of the genetic disorder in the hyperlipidemia extent [3,4]. Down syndrome is the most common recognizable genetic syndrome associated with hematological and immune abnormalities. These include a relatively high predisposition for the development of acute myeloid and lymphoid leukemia, mild to moderate reductions in
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