Uremia-specific Effect on the Arterial Media during Development of Uremic Atherosclerosis in apolipoprotein-E Deficient Mice

Abstract number: P0562

Bro^1,2 S, Borup¹ R, Andersen³ CB, Moeller¹ F, Olgaard² K, Nielsen¹ LB

^{1,2 11}Departments of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark ²²Departments of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark ³³Departments of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E deficient (apoE-/-) mice. To improve understanding of the molecular pathophysiology underlying the development of uremic atherosclerosis, we assessed gene expression patterns in aortas from 5/6 nephrectomized (NX, n= 18) and sham-operated (Sh, n= 18) apoE-/- mice 2 and 12 weeks after surgery. In each group, 3 pools of RNA each from 3 mice were hybridized to Affymetrix GeneChips. Differences in gene expression between NX and Sh mice were verified by real-time RT-PCR. After 12 weeks (when the NX mice showed more atherosclerosis than Sh mice), 24 genes were differentially expressed in NX and Sh mice. Most prominently, 9 genes expressed in muscle cells (including a-actin and myosin) displayed reduced expression (3.3 to 141.7 fold) in NX mouse aortas, whereas osteopontin gene expression was increased 8.7 fold. In a separate comparison of lesioned and nonlesioned areas of non-uremic apoE-/- mouse aortas a reduction of the expression of the muscle cell related genes in lesioned vs. nonlesioned areas was absent or much less pronounced despite a ~15-fold increase in ostepontin gene expression. Immunostaining of aortic sections from NX mice revealed reduced expression of a-actin beneath intimal lesions. Electron microscopy of NX mouse aortas with extensive atherosclerosis revealed makedly altered morphology of the media. After 2 weeks, there was no difference in muscle cell gene expression between NX and Sh mice and no signs of medial smooth muscle cell degeneration. The results suggest that uremic compared to classical atherosclerotic lesion formation is accompanied by accelerated medial smooth muscle cell degeneration.