期刊
REDOX BIOLOGY
卷 46, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2021.102108
关键词
Hyperuricemia; ADMA; DDAH-2; Endothelial dysfunction; Atherosclerosis
资金
- Ministry of Science and Technology of Taiwan [106-2320-B-002-057-MY3, 106-2320-B-002056, 106-2811-B-002-146, 108-2811-B-002-542, 108-2314-B-075-064MY2, 108-2320-B-002-032-MY3]
- Tsou's Foundation [VGHUST104-G7-5-2, VGHUST 105-G7-3-3]
- VGHUST Joint Research Program
Hyperuricemia disrupts the balance of the ADMA/DDAH-2 axis, leading to endothelial dysfunction and accelerating atherosclerosis progression.
Hyperuricemia is closely associated with the mobility and mortality of patients with cardiovascular diseases. However, how hyperuricemia accelerates atherosclerosis progression is not well understood. The balance between asymmetric dimethylarginine (ADMA) and dimethylarginine dimethylaminotransferases (DDAHs) is crucial to regulate vascular homeostasis. Therefore, we investigated the role of the ADMA/DDAH pathway in hyperuricemia-induced endothelial dysfunction and atherosclerosis and the underlying molecular mechanisms in endothelial cells (ECs) and apolipoprotein E-knockout (apoe- /- ) mice. Our results demonstrated that uric acid at pathological concentrations increased the intracellular levels of ADMA and downregulated DDAH-2 expression without affecting DDAH-1 expression. Excess uric acid also reduced NO bioavailability and increased monocyte adhesion to ECs, which were abolished by using the antioxidant N-acetylcysteine, the nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin, or DDAH-2 overexpression. In apoe- /- mice, treatment with oxonic acid, a uricase inhibitor, increased the circulating level of uric acid, cholesterol, and lipid peroxidation; exacerbated systemic and aortic inflammation; and worsened atherosclerosis compared with vehicle-treated apoe- /- mice. Furthermore, oxonic acid-treated apoe- /- mice exhibited elevated ADMA plasma level and downregulated aortic expression of DDAH-2 protein. Notably, DDAH-2 overexpression in the ECs of apoe- /- mice prevented hyperuricemia-induced deleterious effects from influencing ADMA production, lipid peroxidation, inflammation, and atherosclerosis. Collectively, our findings suggest that hyperuricemia disturbs the balance of the ADMA/DDAH-2 axis, results in EC dysfunction, and, consequently, accelerates atherosclerosis.
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