Zhang Wei-Wei, Bai Feng, Wang Jin, Zheng Rong-Hua, Yang Li-Wang, James Erskine A, Zhao Zhi-Qing
Department of Physiology, Shanxi Medical University.
Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China.
Drug Des Devel Ther. 2017 Oct 16;11:3019-3033. doi: 10.2147/DDDT.S144807. eCollection 2017.
Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, <0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, <0.05) and ejection fraction (82%±3% vs 60%±5%, <0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure.
已知血管紧张素II（Ang II）通过引发心脏纤维化参与心室功能障碍和心力衰竭的进展。本研究的目的是证明抗氧化化合物依达拉奉治疗是否通过抑制Ang II AT1受体来减少心脏纤维化并改善心室功能。该研究在大鼠主动脉缩窄（TAC）模型中进行。对照组大鼠接受8周的TAC。在接受治疗的大鼠中，在TAC期间分别通过腹腔注射或灌胃给予依达拉奉（10mg/kg/天）或Ang II AT1受体阻滞剂替米沙坦（10mg/kg/天）。与TAC动物相比，依达拉奉降低了心肌丙二醛水平并增加了超氧化物歧化酶活性。AT1受体的蛋白水平降低，AT2受体上调，AT1与AT2受体的比例降低（0.57±0.2对3.16±0.39，<0.05）以及心肌中局部表达的AT1受体减少证明了这一点。此外，血管紧张素转换酶2的蛋白水平上调。与这些变化一致，依达拉奉显著减少了心肌中巨噬细胞和成肌纤维细胞的数量，同时转化生长因子β1和Smad2/3的水平降低。I型胶原蛋白合成受到抑制，富含胶原蛋白的纤维化减轻。与TAC组相比，心脏收缩功能得以保留，左心室收缩压升高（204±51对110±19mmHg，<0.05）和射血分数增加（82%±3%对60%±5%，<0.05）表明了这一点。在所有测量参数中，替米沙坦治疗提供了与依达拉奉相当的保护水平。综上所述，依达拉奉治疗可改善压力超负荷大鼠模型中的心脏纤维化并改善左心室功能，可能是通过抑制AT1受体介导的信号通路。这些数据表明，在预防心力衰竭中的心功能障碍进展时，依达拉奉可能会与其他现有药物联合使用。
