Back to Search
Start Over
Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension
- Source :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 23 (2021)
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.
- Subjects :
- medicine.medical_specialty
xanthine oxidoreductase
chemistry.chemical_compound
Benzbromarone
Mice
URATv1
uric acid
Internal medicine
pulmonary arterial hypertension
medicine
Animals
Diseases of the circulatory (Cardiovascular) system
Hyperuricemia
Lung
business.industry
arginase
Hypoxia (medical)
medicine.disease
Rats
Arginase
Topiroxostat
Endocrinology
medicine.anatomical_structure
chemistry
RC666-701
Ventricular pressure
Uric acid
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Subjects
Details
- Language :
- English
- ISSN :
- 20479980
- Volume :
- 10
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Accession number :
- edsair.doi.dedup.....d124d74b63ee2f9499a490355ebd2436