Uremia-specific effects in the arterial media during development of uremic atherosclerosis in apolipoprotein E-deficient mice.
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.


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 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.


CONCLUSIONS
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.
Bro
Susanne
S
Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark. susannebro@dadlnet.dk
Borup
Rehannah
R
Andersen
Claus B
CB
Moeller
Flemming
F
Olgaard
Klaus
K
Nielsen
Lars B
LB
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000502:physiology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D020869:Gene Expression Profiling; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000502:physiology; D009392:Nephrectomy; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D017540:Tunica Media / Q000473:pathology / Q000502:physiology; D014511:Uremia / Q000150:complications / Q000235:genetics* / Q000473:pathology*
D000199:Actins; D001057:Apolipoproteins E; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin