Mishima M, Hamada T, Maharani N, Ikeda N, Onohara T, Notsu T, Ninomiya H, Miyazaki S, Mizuta E, Sugihara S, Kato M, Ogino K, Kuwabara M, Hirota Y, Yoshida A, Otani N, Anzai N, Hisatome I
Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Japan.
Drug Res (Stuttg). 2016 May;66(5):270-4. doi: 10.1055/s-0035-1569405. Epub 2016 Feb 24.
Although urate impaired the endothelial function, its underlying mechanism remains unknown. We hypothesized that urate impaired nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) via activation of uric acid transporters (UATs).
In the present study, we studied effects of urate on NO production and eNOS protein expression in HUVEC cells in the presence and absence of urate lowering agents using molecular biological and biochemical assays.
HUVECs expressed the 4 kinds of UATs, URATv1, ABCG2, MRP4 and MCT9. Exposure to urate at 7 mg/dl for 24 h significantly reduced production of NO. Pretreatment with benzbromarone, losartan or irbesartan normalized NO production. The same exposure resulted in dephosphorylation of endothelial NO synthase (eNOS) in HUVECs. Again pretreatment with benzbromarone, losartan or irbesartan abolished this effect.
Urate reduced NO production by impaired phosphorylation of eNOS in HUVEC via activation of UATs, which could be normalized by urate lowering agents.
尽管尿酸会损害内皮功能，但其潜在机制仍不清楚。我们推测尿酸通过激活尿酸转运体（UATs）来损害人脐静脉内皮细胞（HUVECs）中一氧化氮（NO）的生成。
在本研究中，我们使用分子生物学和生化分析方法，研究了在有或没有降尿酸药物存在的情况下，尿酸对HUVEC细胞中NO生成和内皮型一氧化氮合酶（eNOS）蛋白表达的影响。
HUVECs表达4种UATs，即尿酸盐转运体1（URATv1）、乳腺癌耐药蛋白（ABCG2）、多药耐药相关蛋白4（MRP4）和单羧酸转运体9（MCT9）。用7mg/dl尿酸处理24小时可显著降低NO的生成。用苯溴马隆、氯沙坦或厄贝沙坦预处理可使NO生成恢复正常。相同的处理导致HUVECs中内皮型一氧化氮合酶（eNOS）去磷酸化。再次用苯溴马隆、氯沙坦或厄贝沙坦预处理可消除这种作用。
尿酸通过激活UATs损害HUVEC中eNOS的磷酸化，从而降低NO的生成，而降尿酸药物可使其恢复正常。
