Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Biochemistry

Background:

• Uric acid (UA) is known to increase arginase activity, reducing nitric oxide (NO) in endothelial cells.
• The specific role of lung UA in the progression of pulmonary arterial hypertension (PAH) is not well understood.

Purpose of the Study:

• To investigate the hypothesis that elevated lung UA levels contribute to PAH development and progression.
• To explore the therapeutic potential of targeting UA transport and metabolism in PAH.

Main Methods:

• Examined voltage-driven urate transporter 1 (URATv1) expression and UA effects on arginase activity in human pulmonary arterial endothelial cells.
• Utilized SU5416/hypoxia-induced PAH rat models, assessing UA's impact on lung pressure and cGMP levels.
• Investigated the effects of UA transporter inhibitor benzbromarone and arginase inhibitor L-norvaline.
• Induced hyperuricemia in PAH rats using oxonic acid and evaluated the effects of benzbromarone and xanthine oxidoreductase (XOR) inhibitor topiroxostat.
• Assessed XOR-knockout mice under hypoxic conditions.

Main Results:

• UA treatment increased arginase activity and decreased cGMP levels in cultured cells and perfused lungs.
• UA-induced pressor responses in lungs were blocked by benzbromarone and L-norvaline.
• Hyperuricemia in PAH rats exacerbated right ventricular systolic pressure and pulmonary arterial lesions.
• Benzbromarone reduced lung UA and attenuated PAH progression in hyperuricemic rats without affecting XOR activity.
• Topiroxostat and XOR-knockout showed minimal impact on PAH severity, suggesting XOR is not a primary driver.

Conclusions:

• Elevated lung uric acid independently worsens pulmonary arterial hypertension.
• Xanthine oxidoreductase (XOR) plays a minor role in PAH progression.
• Targeting lung UA transporters presents a potential therapeutic strategy for PAH, particularly in patients with hyperuricemia.