Objective--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.

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^-/- 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 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.

Conclusion--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.