Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Hong Kong, China.
Br J Pharmacol. 2011 Sep;164(2b):598-606. doi: 10.1111/j.1476-5381.2011.01416.x.
HMG-CoA reductase inhibitors, statins, with lipid-reducing properties combat against atherosclerosis and diabetes. The favourable modulation of endothelial function may play a significant role in this effect. The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes-associated endothelial dysfunction.
Twelve-week-old db/db diabetic mice were treated with rosuvastatin at 20 mg·kg⁻¹ ·day⁻¹ p.o.for 6 weeks. Isometric force was measured in isolated aortae and renal arteries. Protein expressions including angiotensin II type 1 receptor (AT₁R), NOX4, p22(phox) , p67(phox) , Rac-1, nitrotyrosine, phospho-ERK1/2 and phospho-p38 were determined by Western blotting, while reactive oxygen species (ROS) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay.
Rosuvastatin treatment of db/db mice reversed the impaired ACh-induced endothelium-dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db/db mouse renal arteries and aortae. Rosuvastatin reduced the elevated expressions of AT₁R, p22(phox) and p67(phox) , NOX4, Rac1, nitrotyrosine and phosphorylation of ERK1/2 and p38 MAPK and inhibited ROS production in aortae from db/db mice.
The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability, which is probably achieved by its inhibition of ROS production from the AT₁R-NAD(P)H oxidase cascade.
具有降脂作用的 HMG-CoA 还原酶抑制剂（他汀类药物）可对抗动脉粥样硬化和糖尿病。内皮功能的有利调节可能在这种作用中发挥重要作用。本研究旨在探讨罗苏伐他汀改善糖尿病相关内皮功能障碍的治疗益处的细胞机制。
12 周龄 db/db 糖尿病小鼠经口给予罗苏伐他汀 20mg·kg⁻¹·day⁻¹ 治疗 6 周。在分离的主动脉和肾动脉中测量等长力。通过 Western blot 测定血管紧张素 II 型 1 受体（AT₁R）、NOX4、p22(phox)、p67(phox)、Rac-1、硝基酪氨酸、磷酸化 ERK1/2 和磷酸化 p38 的蛋白表达，而血管壁中活性氧（ROS）的积累则通过二氢乙啶荧光和荧光素测定来评估。
罗苏伐他汀治疗可逆转 db/db 小鼠的肾动脉和主动脉中乙酰胆碱诱导的内皮依赖性舒张功能障碍，并防止 db/db 小鼠肾动脉和主动脉对血管紧张素 II 和苯肾上腺素的过度收缩。罗苏伐他汀降低了 db/db 小鼠主动脉中 AT₁R、p22(phox)和 p67(phox)、NOX4、Rac1、硝基酪氨酸和 ERK1/2 和 p38 MAPK 磷酸化的升高，并抑制了 db/db 小鼠主动脉中 ROS 的产生。
罗苏伐他汀的血管保护作用归因于 NO 生物利用度的增加，这可能是通过其抑制 AT₁R-NAD(P)H 氧化酶级联反应中的 ROS 产生来实现的。
