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J. Biol. Chem., Vol. 266, Issue 13, 8604-8608, 05, 1991
GN Rao, MA Corson and BC Berk
Recent data suggest that uric acid is generated locally in the vessel wall
by the action of xanthine oxidase. This enzyme, activated during
ischemia/reperfusion by proteolytic conversion of xanthine dehydrogenase,
catalyzes the oxidation of xanthine, thereby generating free radicals and
uric acid. Because of the potential role of ischemia/reperfusion in
vascular disease, we studied the effects of uric acid on rat aortic
vascular smooth muscle cell (VSMC) growth. Uric acid stimulated VSMC DNA
synthesis, as measured by [3H]thymidine incorporation, in a
concentration-dependent manner with half-maximal activity at 150 microM.
Maximal induction of DNA synthesis by uric acid (250 microM) was
approximately 70% of 10% calf serum and equal to 10 ng/ml platelet-derived
growth factor (PDGF) AB or 20 ng/ml fibroblast growth factor. Neither uric
acid precursors (xanthine and hypoxanthine) nor antioxidants (ascorbic
acid, glutathione, and alpha-tocopherol) were mitogenic for VSMC. Uric acid
was mitogenic for VSMC but not for fibroblasts or renal epithelial cells.
The time course for uric acid stimulation of VSMC growth was slower than
serum, suggesting induction of an autocrine growth mechanism. Exposure of
quiescent VSMC to uric acid stimulated accumulation of PDGF A-chain mRNA
(greater than 5-fold at 8 h) and secretion of PDGF-like material in
conditioned medium (greater than 10-fold at 24 h). Uric acid-induced
[3H]thymidine incorporation was markedly inhibited by incubation with
anti-PDGF A- chain polyclonal antibodies. Thus uric acid stimulates VSMC
growth via an autocrine mechanism involving PDGF A-chain. These findings
suggest that generation of uric acid during ischemia/reperfusion
contributes to atherogenesis and intimal proliferation following arterial
injury.
Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
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