Hyperuricemia induces endothelial dysfunction and accelerates atherosclerosis by disturbing the asymmetric dimethylarginine/dimethylarginine dimethylaminotransferase 2 pathway

Abstract

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.

High Level of Serum Uric Acid induced Monocyte Inflammation is Related to Coronary Calcium Deposition in the Middle-Aged and Elder Population of China: A five-year Prospective Cohort Study

“… 38–40 In this study, we focused on asymptomatic middle-aged and elderly participants because aging is considered as a chronic inflammatory state which plays a vital role in the pathogenesis and development of asymptomatic hyperuricemia and coronary calcification. 22 , 24 The results of our five-year follow-up and another observational study have shown that high serum uric acid levels are an independent risk factor for coronary calcification in asymptomatic middle-aged and elderly population. The relative mRNA expression levels in PBMCs of the four groups of patients (NC, HUA, CAC and HUA-CAC patients) were compared to verify the results of previous bioinformatics analysis on the common target genes of HUA and CAS.…”

“… 22 , 23 Meanwhile, many studies have shown that the pathogenesis of HUA is related to inflammation, oxidative stress, insulin resistance and so on. 8 , 24 …”

Lactobacillus paracasei X11 Ameliorates Hyperuricemia and Modulates Gut Microbiota in Mice

“…In clinical practice and research, HUA is generally reported when the serum urate is above 0.42 mmol/L (7 mg/dl) for men or 0.36 mmol/L (6 mg/dl) for women ( 4 ). It may result in the deposition of UA crystals, which promotes high comorbidity burden and finally leads to tissue damage such as gout ( 5 ), atherosclerosis ( 6 ), type 2 diabetes mellitus ( 7 ), vascular damage ( 8 ), and chronic kidney disease ( 9 ). The incidence of HUA has been remarkably increased by about 20% worldwide ( 10 ), and the patients have become younger, which is of concern ( 11 , 12 ), so HUA has emerged as a public health challenge.…”

Effectiveness of Urate-Lowering Therapy for Renal Function in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Clinical Trials

“…A cross-sectional study in patients with unilateral small kidney or renal agenesis conducted by Yazici et al demonstrated that the SUA level was positively correlated with arterial stiffness ( Yazici et al, 19932017 ). Mechanistic studies have shown that uric acid causes endothelial dysfunction, resulting in cardiovascular events ( Khosla et al, 2005 ; Liang et al, 2015 ; Lee et al, 2021 ; Singh et al, 2021 ). In our meta-analysis, we found that allopurinol might slightly reduce the risk of cardiovascular complications in only three RCTs.…”