Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada.
Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1809-16. doi: 10.1161/ATVBAHA.112.252973. Epub 2012 Jun 21.
Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor-coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis.
We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (P<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (P<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (P<0.05).
These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.
尿皮质素 II（UII）是一种有效的血管活性肽，与尿皮质素受体偶联受体-14（称为 UT）结合，在人类和实验动物中发挥广泛的作用。我们测试了这样一个假设，即 UII 基因缺失或 UT 阻断可改善实验性动脉粥样硬化。
与野生型相比，UII 基因敲除小鼠体重增加、内脏脂肪、血压、循环血浆脂质和促动脉粥样硬化细胞因子减少，葡萄糖耐量改善（P<0.05）。载脂蛋白 E 敲除后 UII 的缺失导致血清细胞因子、脂肪因子和主动脉粥样硬化与载脂蛋白 E 敲除小鼠相比显著减少。同样，用 UT 拮抗剂 SB657510A 治疗高脂饮食喂养的载脂蛋白 E 敲除小鼠可减轻体重增加、内脏脂肪和高脂血症，改善葡萄糖耐量（P<0.05），并减轻动脉粥样硬化的发生和进展。UT 拮抗剂还降低了主动脉细胞外信号调节激酶 1/2 磷酸化和氧化剂形成以及血清细胞因子水平（P<0.05）。
这些发现首次证明了 UII 基因缺失在动脉粥样硬化中的作用，并表明使用旨在阻断 UII 途径的药物可能为治疗动脉粥样硬化及其相关前体，如肥胖、高脂血症、糖尿病和高血压提供一种新方法。
