The Apolipoprotein E Knockout Mouse: A Model Documenting Accelerated Atherogenesis In Uremia

Abstract

ABSTRACT. Rodents do not develop spontaneous atherosclerosis. Currently, there is no good animal model to study the effect of uremia on atherosclerosis. This study evaluated whether apolipoprotein E knockout (Apoe−/−) mice are useful to study the effect of renal dysfunction on cardiovascular risk. Apoe−/− mice have decreased serum apolipoprotein E and exhibit lipid abnormalities and atherosclerosis even on a low-cholesterol diet. Ten-wk-old Apoe−/− mice were subtotally nephrectomised (SNX Apoe−/−; n = 8), uninephrectomised (UNX Apoe−/−; n = 5), or sham-operated (sham Apoe−/−; n = 5) and compared with their genetic controls (SNX C57/BL6; UNX C57/BL6; sham C57/BL6). After 12 wk, BP was measured intraarterially, blood samples were taken, and the experiment was terminated by perfusion fixation. The heart weight was determined, and quantitative morphologic analysis of intramyocardial arteries and aortic changes was performed. At the end of the experiment, heart weight and relative left ventricular weight were comparable in all groups. Intraarterial BP was somewhat higher in Apoe−/− mice compared with controls. Baseline serum cholesterol and triglyceride levels were higher in Apoe−/− mice than in C57/BL6. Atherosclerotic plaques were not present in sham or UNX C57/BL6, but minor plaque formation was noted in some SNX control animals. In contrast, beginning plaques were seen even in untouched Apoe−/− mice, and strikingly increased plaque formation was noted in UNX and SNX Apoe−/− mice. Maximal plaque diameter (cross-section) was 37 ± 74 μm in SNX C57/BL6, 191 ± 90 μm in sham Apoe−/−, 323 ± 66 μm in UNX Apoe−/−, and 457 ± 17 μm in SNX Apoe−/−. The plaque morphology corresponded with that of early plaques characterized by foam cells and virtual absence of lymphocytes or smooth muscle cell infiltration. In conclusion, even mild renal dysfunction, i.e., after uninephrectomy, causes a dramatic increase in plaque size and aggressive morphology (foam cell rich soft plaques) in the animal model of the Apoe−/− mouse. E-mail: Kerstin.Amann@patho.imed.uni-erlangen.de