Department of Biology, Kangwon National University, Chuncheon 200-701, Republic of Korea.
Int J Mol Med. 2013 Apr;31(4):803-10. doi: 10.3892/ijmm.2013.1261. Epub 2013 Jan 30.
Elevated plasma cholesterol is a hallmark of numerous cardiovascular diseases that are closely linked to endothelial dysfunction indicating decreased nitric oxide (NO) production in the endothelium. It has been previously demonstrated that piceatannol-3'-O-β-D-glucopyranoside (PG) inhibits arginase activity and reciprocally regulates NO production. Here, we aimed to ascertain whether PG ameliorates vascular function in wild-type (WT) and atherogenic model mice [apolipoprotein E-null mice (ApoE-/-)] and to investigate the possible underlying mechanism. Preincubation of aortic vessels from WT mice fed a normal diet (ND) with PG attenuated vasoconstriction response to U46619 and phenylephrine (PE), while the vasorelaxant response to acetylcholine (Ach) was markedly enhanced in an endothelium-dependent manner. However, the endothelium-independent NO donor, sodium nitroprusside (SNP), did not change vessel reactivity. In thoracic aorta from ApoE-/- mice, a high-cholesterol diet (HCD) induced an increase in arginase activity, a decrease in NO release and an increase in reactive oxygen species generation that was reversed by treatment with PG. The effect of PG was associated with enhanced stability of the eNOS dimer and was not dependent on the expression levels of arginase II and eNOS proteins, although eNOS expression was increased in ApoE-/- mice fed an HCD. Furthermore, PG treatment attenuated the PE-dependent contractile response, and significantly improved the Ach-dependent vasorelaxation response in aortic rings from ApoE-/- mice fed an HCD. On the other hand, PG incubation neither altered the contractile response to a high K+ solution nor the relaxation response to SNP. When analyzing the L-arginine content using high-performance liquid chromatography, PG incubation increased the intracellular L-arginine concentration. PG administration in the drinking water significantly reduced fatty streak formation in ApoE-/- mice fed an HCD. These data indicate that PG improves the pathophysiology of cholesterol-mediated endothelial dysfunction. Therefore, we conclude that the development of PG as a novel effective therapy for preventing atherosclerotic diseases is warranted.
血浆胆固醇升高是许多心血管疾病的标志,这些疾病与内皮功能障碍密切相关,表明内皮一氧化氮(NO)生成减少。先前已经证明,白藜芦醇-3'-O-β-D-吡喃葡萄糖苷(PG)抑制精氨酸酶活性,并反向调节 NO 生成。在这里,我们旨在确定 PG 是否改善野生型(WT)和动脉粥样硬化模型小鼠[载脂蛋白 E 缺陷型小鼠(ApoE-/-)]的血管功能,并探讨可能的潜在机制。用 PG 预孵育正常饮食(ND)喂养的 WT 小鼠的主动脉血管可减轻对 U46619 和苯肾上腺素(PE)的血管收缩反应,而乙酰胆碱(Ach)的血管舒张反应则以内皮依赖性方式显著增强。然而,内皮非依赖性 NO 供体硝普钠(SNP)并没有改变血管反应性。在 ApoE-/- 小鼠的胸主动脉中,高胆固醇饮食(HCD)诱导精氨酸酶活性增加、NO 释放减少和活性氧生成增加,这些变化可被 PG 逆转。PG 的作用与 eNOS 二聚体稳定性的增强有关,而不依赖于精氨酸酶 II 和 eNOS 蛋白的表达水平,尽管 HCD 喂养的 ApoE-/- 小鼠中 eNOS 表达增加。此外,PG 处理可减弱 PE 依赖性收缩反应,并显著改善 HCD 喂养的 ApoE-/- 小鼠主动脉环中 Ach 依赖性血管舒张反应。另一方面,PG 孵育既不改变对高 K+溶液的收缩反应,也不改变对 SNP 的舒张反应。使用高效液相色谱法分析 L-精氨酸含量时,PG 孵育增加了细胞内 L-精氨酸浓度。在饮用水中给予 PG 可显著减少 HCD 喂养的 ApoE-/- 小鼠中的脂肪条纹形成。这些数据表明,PG 改善了胆固醇介导的内皮功能障碍的病理生理学。因此,我们得出结论,开发 PG 作为预防动脉粥样硬化疾病的新型有效疗法是合理的。