Abdali Nibrass Taher, Yaseen Awny H, Said Eman, Ibrahim Tarek M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Department of Histology and Cytology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2017 Apr;390(4):409-422. doi: 10.1007/s00210-017-1343-x. Epub 2017 Jan 18.
The current study was designed to investigate the potential beneficial therapeutic outcome of Rho kinase inhibitor (fasudil) against hypercholesterolemia-induced myocardial and vascular injury in rabbits together with diet modification. Sixteen male rabbits were randomly divided into four groups: normal control group which received standard rabbit chow, hypercholesterolemic control group, and treated groups which received cholesterol-rich rabbit chow (1.5% cholesterol) for 8 weeks. Treated groups received either fasudil (100 mg/kg/day) or rosuvastatin (2.5 mg/kg/day) starting from the ninth week for further 4 weeks with interruption of the cholesterol-rich chow. Biochemical assessment of serum cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and myocardial oxidative/antioxidant biomarkers malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH), besides biochemical assessment of serum nitric oxide (NO), creatine kinase (CK), and lactate dehydrogenase (LDH) activities and serum total antioxidant capacity (TAC), was conducted. Serum vascular cell adhesion molecule 1 (VCAM-1) and serum Rho-associated protein kinase 1 (ROCK-1) were also evaluated along with histopathological examination of aorta specimens. Fasudil administration significantly decreased serum cholesterol, triglyceride (TG), and LDL and significantly increased serum HDL, with concomitant decrease in serum CK and LDH activities, NO, and restoration of serum TAC. Myocardial MDA significantly declined; SOD activity and GSH contents were restored. Serum ROCK-1 and VCAM-1 levels significantly declined as well. Vascular improvement was confirmed with histopathological examination, which revealed normal aortic intema with the absence of atheromas. Fasudil has promising anti-atherogenic activity mediated primarily via alleviation of hypercholesterolemia-induced oxidative stress and modulation of inflammatory response.
本研究旨在探讨Rho激酶抑制剂（法舒地尔）联合饮食调整对高胆固醇血症诱导的家兔心肌和血管损伤的潜在有益治疗效果。16只雄性家兔随机分为四组：正常对照组给予标准兔饲料，高胆固醇血症对照组，以及接受富含胆固醇的兔饲料（1.5%胆固醇）8周的治疗组。从第9周开始，治疗组分别给予法舒地尔（100mg/kg/天）或瑞舒伐他汀（2.5mg/kg/天），持续4周，同时中断富含胆固醇的饲料。除了对血清一氧化氮（NO）、肌酸激酶（CK）、乳酸脱氢酶（LDH）活性和血清总抗氧化能力（TAC）进行生化评估外，还对血清胆固醇、甘油三酯、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）以及心肌氧化/抗氧化生物标志物丙二醛（MDA）、超氧化物歧化酶（SOD）和还原型谷胱甘肽（GSH）进行生化评估。还评估了血清血管细胞粘附分子1（VCAM-1）和血清Rho相关蛋白激酶1（ROCK-1），并对主动脉标本进行了组织病理学检查。给予法舒地尔可显著降低血清胆固醇、甘油三酯（TG）和LDL，显著升高血清HDL，同时降低血清CK和LDH活性、NO，并恢复血清TAC。心肌MDA显著下降；SOD活性和GSH含量恢复。血清ROCK-1和VCAM-1水平也显著下降。组织病理学检查证实血管有所改善，显示主动脉内膜正常，无动脉粥样硬化。法舒地尔具有有前景的抗动脉粥样硬化活性，主要通过减轻高胆固醇血症诱导的氧化应激和调节炎症反应来介导。
