Spiga Rosangela, Marini Maria Adelaide, Mancuso Elettra, Di Fatta Concetta, Fuoco Anastasia, Perticone Francesco, Andreozzi Francesco, Mannino Gaia Chiara, Sesti Giorgio
From the Department of Medical and Surgical Sciences, University Magna-Græcia of Catanzaro, Italy (R.S., E.M., C.D.F., A.F., F.P., F.A., G.C.M., G.S.); and Department of Systems Medicine, University of Rome Tor Vergata, Italy (M.A.M.).
Arterioscler Thromb Vasc Biol. 2017 Jun;37(6):1241-1249. doi: 10.1161/ATVBAHA.117.309128. Epub 2017 Apr 13.
Serum uric acid (UA) has been associated with increased risk of cardiovascular and metabolic diseases. However, the causal mechanisms linking elevated UA levels to cardio-metabolic diseases are still unsettled. One potential explanation for how UA might contribute to cardio-metabolic disease might be its ability to induce systemic inflammation.
Herein, we report a positive relationship between serum UA and acute-phase reactants, such as high-sensitivity C-reactive protein, fibrinogen, ferritin, complement C3, and erythrocyte sedimentation rate, in a cohort of 2731 nondiabetic adults. The relationship remains significant after adjustment for several confounders, including age, sex, adiposity, anti-hypertensive treatments or diuretics use. To confirm the existence of a causal relationship, we examined the effect of UA on the expression of inflammatory biomarkers in human hepatoma HepG2 cells and characterized the signaling pathway by which UA acts. We show that UA stimulates the expression of C-reactive protein, fibrinogen, ferritin, and complement C3 in a dose-dependent fashion. The proinflammatory effects of UA were abrogated by benzbromarone, a specific inhibitor of UA transporters. Exposure of cells to UA resulted in activation of the IκB kinase/IκBα/NF-κB signaling pathway that was attenuated by benzbromarone. The effect of UA was completely blocked by the antioxidant -acetylcysteine.
These in vivo and in vitro data suggest that hyperuricemia might induce the expression of hepatic inflammatory molecules by activating the proinflammatory NF-κB signaling cascade. Because inflammation has an important pathogenetic role in metabolic and cardiovascular disease, our study may help understanding the mechanism by which hyperuricemia may contribute to organ damage.
血清尿酸（UA）与心血管疾病和代谢性疾病风险增加有关。然而，将尿酸水平升高与心脏代谢疾病联系起来的因果机制仍未明确。尿酸可能导致心脏代谢疾病的一种潜在解释可能是其诱导全身炎症的能力。
在此，我们报告了在2731名非糖尿病成年人队列中，血清尿酸与急性期反应物（如高敏C反应蛋白、纤维蛋白原、铁蛋白、补体C3和红细胞沉降率）之间存在正相关关系。在对包括年龄、性别、肥胖、抗高血压治疗或利尿剂使用等多个混杂因素进行调整后，这种关系仍然显著。为了证实因果关系的存在，我们研究了尿酸对人肝癌HepG2细胞中炎症生物标志物表达的影响，并确定了尿酸发挥作用的信号通路。我们发现尿酸以剂量依赖的方式刺激C反应蛋白、纤维蛋白原、铁蛋白和补体C3的表达。尿酸转运体的特异性抑制剂苯溴马隆可消除尿酸的促炎作用。细胞暴露于尿酸会导致IκB激酶/IκBα/NF-κB信号通路激活，而苯溴马隆可减弱该通路的激活。尿酸的作用被抗氧化剂N-乙酰半胱氨酸完全阻断。
这些体内和体外数据表明，高尿酸血症可能通过激活促炎的NF-κB信号级联反应诱导肝脏炎症分子的表达。由于炎症在代谢性疾病和心血管疾病中具有重要的发病机制作用，我们的研究可能有助于理解高尿酸血症可能导致器官损伤的机制。
