Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression

Rao Gadiparthi, Marshall A. Corson, Bradford C. Berk

Research output: Contribution to journalArticle

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Abstract

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 μM. Maximal induction of DNA synthesis by uric acid (250 MM) was ∼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 α-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 (>5-fold at 8 h) and secretion of PDGF-like material in conditioned medium (>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 intimai proliferation following arterial injury.

Original languageEnglish (US)
Pages (from-to)8604-8608
Number of pages5
JournalJournal of Biological Chemistry
Volume266
Issue number13
StatePublished - May 5 1991
Externally publishedYes

Fingerprint

Cell proliferation
Uric Acid
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Cell Proliferation
Cell growth
Reperfusion
Xanthine
Ischemia
Growth
Thymidine
platelet-derived growth factor A
Xanthine Dehydrogenase
Hypoxanthine
Tocopherols
Fibroblast Growth Factors
Xanthine Oxidase
DNA
Platelet-Derived Growth Factor

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. / Gadiparthi, Rao; Corson, Marshall A.; Berk, Bradford C.

In: Journal of Biological Chemistry, Vol. 266, No. 13, 05.05.1991, p. 8604-8608.

Research output: Contribution to journalArticle

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