Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells

Abstract

Elevated levels of serum uric acid (UA) are commonly associated with primary pulmonary hypertension but have generally not been thought to have any causal role. Recent experimental studies, however, have suggested that UA may affect various vasoactive mediators. We therefore tested the hypothesis that UA might alter nitric oxide (NO) levels in pulmonary arterial endothelial cells (PAEC). In isolated porcine pulmonary artery segments (PAS), UA (7.5 mg/dl) inhibits acetylcholine-induced vasodilation. The incubation of PAEC with UA caused a dose-dependent decrease in NO and cGMP production stimulated by bradykinin or Ca(2+)-ionophore A23187. We explored cellular mechanisms by which UA might cause reduced NO production focusing on the effects of UA on the l-arginine-endothelial NO synthase (eNOS) and l-arginine-arginase pathways. Incubation of PAEC with different concentrations of UA (2.5-15 mg/dl) for 24 h did not affect l-[(3)H]arginine uptake or activity/expression of eNOS. However, PAEC incubated with UA (7.5 mg/dl; 24 h) released more urea in culture media than control PAEC, suggesting that arginase activation might be involved in the UA effect. Kinetic analysis of arginase activity in PAEC lysates and rat liver and kidney homogenates demonstrated that UA activated arginase by increasing its affinity for l-arginine. An inhibitor of arginase (S)-(2-boronoethyl)-l-cysteine prevented UA-induced reduction of A23187-stimulated cGMP production by PAEC and abolished UA-induced inhibition of acetylcholine-stimulated vasodilation in PAS. We conclude that UA-induced arginase activation is a potential mechanism for reduction of NO production in PAEC.

Uric Acid as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Sickle Cell Disease

“…For example, UA increases cyclo-oxygenase-2 and ET-1 expression in vascular smooth muscle cells (VSMC) [18,19]. UA also inhibits vasodilatation in the lung by reducing nitric oxide production by endothelial cells [20]. In rats, acute elevation of UA with uricase inhibitor allantoxanamide leads to increase in medial thickness of pulmonary arterioles [18].…”

Uric acid and the cardiovascular profile of African and Caucasian men

“…32,33 Besides its possible direct effect on vascular smooth muscle cells proliferation and migration, UA may also exert other detrimental effects on the vascular system. It is speculated that UA alters the release of endothelial nitric oxide, 34,35 allowing the endothelium to convert from a vasoprotective environment to one that is vasoconstrictive, procoagulant and antifibrinolytic. 36 Although this crosssectional study limits us to draw any conclusions, the latter mentioned relationship might suggest a possible mechanistic link between hyperuricemia and hypertension.…”

Uric acid transport and disease

“…For instance, in pulmonary endothelial cells, uric acid reduces NO production by a mechanism that depends on uric acid increasing the activity of arginase, which diverts l-arginine to urea production instead of to NO production by eNOS ( Figure 2C and ref. 41).…”