ABSTRACT
Cardiovascular disease (CVD) is the most frequent cause of morbidity and mortality in chronic renal failure (CRF) patients. Accelerated calcifying atherosclerosis, medial calcification, and valvular calcification are hallmarks of CVD in the dialysis population. The mechanisms by which uraemia promotes vascular calcification and the relationship between arterial wall calcification and atherosclerosis are poorly understood. We surgically induced CRF in apolipoprotein E knockout (apoE-/-) mice to study a possible acceleration of aortic atherosclerosis, the degree and type of vascular calcification as well as factors involved in the calcification process. Finally we investigated appropriate treatment measures. Atherosclerotic lesions in the thoracic aorta were significantly larger in uraemic apoE-/- mice than in non-uraemic controls. The relative proportion of the calcified area to the total surface area of both atherosclerotic lesions and lesion-free vascular tissue was increased in the aortic root of uraemic apoE-/- mice when compared with controls. The accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression, indicating enhanced oxidative stress, and an increase in plaque collagen content, indicating changes in plaque composition. N-acetylcysteine (NAC) treatment slowed the rapid progression of atherosclerotic lesions and reversed the increase in plaque collagen content compared with placebo treatment. NAC-treatment also reduced nitrotyrosine expression in uremic apoE-/- mice whereas the degree of macrophage infiltration was unchanged. Sevelamer treatment delayed not only vascular calcification but also atherosclerotic lesion progression in uraemic apoE-/- mice. These treatment effects also were associated with diminished oxidative stress and were independent of cholesterol lowering. We anticipate that this experimental model will prove to be useful to test other treatment strategies aimed at decreasing the accelerated atherosclerosis and arterial calcification of the uraemic state.
