Uremia-Specific Effects in the Arterial Media During Development of Uremic Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

Uremia accelerates formation of atherosclerosis-like lesions in apolipoprotein E-deficient (apoE(-/-)) mice. In this study, we compared gene expression patterns in classical and uremic atherosclerosis. High-density oligonucleotide microarray analyses were performed with aortic RNA from 5/6 nephrectomized (NX) and sham-operated mice. After 12 weeks, NX apoE(-/-) mice had more atherosclerosis and 24 genes were differentially expressed as compared with sham apoE(-/-) mice. Nine genes expressed in muscle cells displayed reduced expression (3.3- to 142-fold, P<0.05), whereas osteopontin gene expression was increased 8.7-fold (P<0.05) in NX mice. Studies of NX wild-type mice suggested that the changes in NX apoE(-/-) mice were dependent on hypercholesterolemia. Nevertheless, lesioned versus nonlesioned areas of aortas from nonuremic apoE(-/-) mice with classical atherosclerosis displayed less pronounced reductions in expression of the muscle cell related genes than seen in NX apoE(-/-) mice even though the osteopontin gene expression was increased approximately 15-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(-/-) mice. The results suggest that uremic vasculopathy in apoE(-/-) mice, in addition to intimal atherosclerosis, is characterized by a uremia-specific medial smooth muscle cell degeneration, which appears to be accentuated by hypercholesterolemia.