Abstract. Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E-deficient mice, but the mechanism is unknown. The recruitment of inflammatory cells in the arterial wall by vascular adhesion molecules plays a key role in the formation of classical atherosclerosis. This study examines whether the expression of vascular adhesion molecules is increased in uremic atherosclerosis. Uremia was induced by 5/6 nephrectomy; control mice were sham-operated. After 2 wk of uremia, no lesion formation could be demonstrated in uremic or control mice. After 12 wk, aortas from uremic mice had a 9.8-fold increase of the aortic plaque area fraction compared with control mice (P Ͻ 0.0001). The aortic expression of intercellular adhesion molecule-1 (ICAM-1) mRNA in uremic mice was 215 Ϯ 31% (P Ͻ 0.05) and 243 Ϯ 55% (P Ͻ 0.05) of that in controls after 2 and 12 wk, respectively (n ϭ 9 ϫ 4). In contrast, aortic expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA in uremic mice was unchanged after 2 wk but increased to 237 Ϯ 40% (P Ͻ 0.01) of that in control mice after 12 wk. On immunohistochemistry of aortas from uremic mice, ICAM-1 was predominantly present in endothelial cells both in nonlesioned and lesioned aortas, whereas VCAM-1 was predominantly present in the medial smooth muscle cell layer in lesioned aortas. The plasma concentration of soluble ICAM-1 (sICAM-1) (but not of sVCAM-1) was slightly elevated after 2 wk of uremia. In contrast, both sICAM-1 and sVCAM-1 plasma concentrations were markedly higher in uremic than control mice after 12 wk. These results suggest that uremic atherosclerosis is preceded by an upregulation of ICAM-1 expression in arterial endothelium and that formation of early uremic lesions is accompanied by upregulation of VCAM-1 expression in the medial smooth muscle cell layer.

Objective-Uremia accelerates formation of atherosclerosis-like lesions in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. In this study, we compared gene expression patterns in classical and uremic atherosclerosis. Methods and Results-High-density oligonucleotide microarray analyses were performed with aortic RNA from 5/6 nephrectomized (NX) and sham-operated mice. After 12 weeks, NX apoE Ϫ/Ϫ mice had more atherosclerosis and 24 genes were differentially expressed as compared with sham apoE Ϫ/Ϫ mice. Nine genes expressed in muscle cells displayed reduced expression (3.3-to 142-fold, PϽ0.05), whereas osteopontin gene expression was increased 8.7-fold (PϽ0.05) in NX mice. Studies of NX wild-type mice suggested that the changes in NX apoE Ϫ/Ϫ mice were dependent on hypercholesterolemia. Nevertheless, lesioned versus nonlesioned areas of aortas from nonuremic apoE Ϫ/Ϫ mice with classical atherosclerosis displayed less pronounced reductions in expression of the muscle cell related genes than seen in NX apoE Ϫ/Ϫ mice even though the osteopontin gene expression was increased Ϸ15-fold. Electron microscopy showed more vacuolized and necrotic smooth muscle cells within the media underneath both nonlesioned and lesioned intima in NX than in sham apoE Ϫ/Ϫ mice. Conclusion-The results suggest that uremic vasculopathy in apoEϪ/Ϫ mice, in addition to intimal atherosclerosis, is characterized by a uremia-specific medial smooth muscle cell degeneration, which appears to be accentuated by hypercholesterolemia. Key Words: renal failure Ⅲ uremia Ⅲ atherosclerosis Ⅲ vascular smooth muscle cells Ⅲ apolipoprotein E-deficient mice T he cardiovascular mortality rate is increased Ϸ300-fold in 30-year-old individuals on dialysis compared with individuals without renal disease, 1 and even mild renal failure is an independent risk factor of cardiovascular disease. 2,3 Although renal dysfunction often is accompanied by dyslipidemia, hypertension, and diabetes, the high prevalence of cardiovascular disease in patients with renal disease cannot be explained by the classical risk factors alone. 4,5 Thus, renal dysfunction is also associated with nontraditional cardiovascular risk factors, including activation of the renin angiotensin system. 6 Even though renal failure is accompanied by calcification of arteries, 7 it has been controversial whether uremia might accelerate formation of atherosclerosis. Recent experiments from three different groups (including ours) 8 -10 have disclosed that 5/6 nephrectomy (NX) in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice accelerates formation of intimal lesions in aorta. NX apoE Ϫ/Ϫ mice develop 6-to 10-times more lesions than sham-operated control mice despite similar blood pressure and plasma homocysteine concentrations, and only minor differences in plasma lipoprotein concentrations. 8,11 The NX mice are also characterized by a low body weight, reduced blood hemoglobin, and increased plasma calcium ϫ phosphate product. 8,11 Intimal lesions in NX mice are qualitatively similar to those in classical atheroscler...

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