目的 探讨依达拉奉（Eda）调节Notch/发状分裂相关增强子1 (Hes-1)信号通路对慢性心力衰竭（CHF）大鼠心肌损伤的影响及机制。方法 建立CHF大鼠模型，将大鼠分为假手术（S）组、模型（M）组、Eda低剂量（Eda-L）组、Eda中剂量（Eda-M）组、Eda高剂量（Eda-H）组和Eda-H + Notch信号通路抑制剂DAPT（Eda-H + DAPT）组，每组25只。超声心动图检测大鼠左心室舒张末期内径（LVEDd）、左心室收缩末期内径（LVEDs）和左心室射血分数（LVEF）水平；ELISA检测血清肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1β、IL-6、丙二醛（MDA）、超氧化物歧化酶（SOD）和血管紧张素（Ang）Ⅱ水平；2，3，5-三苯基氯化四氮唑（TTC）染色观察心肌梗死情况；HE染色、TUNEL染色和Masson染色分别观察心肌组织形态变化、心肌细胞凋亡和心肌纤维化情况；免疫组织化学检测心肌组织Ⅰ型胶原和血管紧张素转化酶2（ACE2）蛋白表达；Western blotting检测心肌组织Notch 1、Hes-1、转化生长因子-β1（TGF-β1）、Bcl-2、Bax和Caspase-3蛋白表达。结果 与假手术组相比，模型组大鼠心肌细胞分布杂乱，出现严重的炎性症状；血管周围区域和心肌间有大量的蓝色胶原沉积；LVEDd、LVEDs、TNF-α、IL-1β、IL-6、MDA和Ang Ⅱ水平、心肌梗死面积、心肌细胞凋亡率、Ⅰ型胶原、Bax、Caspase-3和TGF-β1蛋白表达显著增加（P<0.05），LVEF、SOD水平，ACE2、Bcl-2、Notch 1和Hes-1蛋白表达显著降低（P<0.05）。与模型组相比，Eda-L组、Eda-M组和Eda-H组心肌组织损伤减轻，炎性细胞浸润减少，胶原沉积减少；LVEDd、LVEDs、TNF-α、IL-1β、IL-6、MDA和Ang Ⅱ水平，心肌梗死面积，心肌细胞凋亡率，Ⅰ型胶原、Bax、Caspase-3和TGF-β1蛋白表达依次降低（P<0.05）；LVEF、SOD水平，ACE2、Bcl-2、Notch 1和Hes-1蛋白表达依次增加（P<0.05）。Notch信号通路抑制剂DAPT逆转Eda对CHF大鼠心肌损伤的保护作用（P<0.05）。结论Eda可能通过激活Notch/Hes-1信号通路改善CHF大鼠心肌损伤。

Objective To investigate the effect and mechanism of edaravone (Eda) on myocardial injury in chronic heart failure (CHF) rats by regulating Notch/Hes-1 signaling pathway.   Methods The CHF rat model was established and the rats were separated into sham surgery (S) group, model(M) group, low dose Eda (Eda-L) group, medium dose Eda (Eda-M) group, high dose Eda (Eda-H) group, and Eda-H + Notch signal pathway inhibitor DAPT (Eda-H + DAPT) group, with 25 rats in each group. Echocardiography was applied to detect the levels of left ventricular end diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), and left ventricular ejection fraction (LVEF) in rats. ELISA was applied to detect levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD), and angiotensin Ⅱ (Ang Ⅱ) in serum. Myocardial infarction was observed by 2,3,5-triphenyl tetrazolium chloride(TTC) staining. HE staining, TUNEL staining and Masson staining were applied to observe the morphological changes of myocardial tissue, myocardial cell apoptosis and myocardial fibrosis respectively. immunohistochemistry was applied to detect the expression of collagen Ⅰ and angiotensin converting enzyme 2 (ACE2) proteins in myocardial tissue. Western blotting was applied to detect the expression of Notch 1, Hes-1, transforming growth factor-β1 (TGF-β1), Bcl-2, Bax, and Caspase-3 proteins in myocardial tissue.   Results Compared with the sham group, the distribution of cardiomyocytes in model group was disordered, and severe inflammatory symptoms. There was a large amount of blue collagen deposition between the perivascular area and the myocardium. The LVEDd, LVEDs, TNF-α, IL-1β, IL-6, MDA and Ang Ⅱ levels, myocardial infarction size, cardiomyocyte apoptosis rate, Collagen Ⅰ, Bax, Caspase-3 and TGF-β1 protein expressions increased obviously (P<0.05), the LVEF, SOD levels, ACE2, Bcl-2, Notch 1, and Hes-1 protein expressions were obviously reduced (P<0.05). Compared with the model group, the myocardial tissue damage was reduced in the Eda-L, Eda-M, and Eda-H groups, with reduced inflammatory cell infiltration and collagen deposition; The LVEDd, LVEDs, TNF-α, IL-1β, IL-6, MDA and Ang Ⅱ levels, myocardial infarction size, cardiomyocyte apoptosis rate, collagen Ⅰ, Bax, Caspase-3 and TG-β1 protein expressions reduced obviously(P<0.05), the LVEF, SOD levels, ACE2, Bcl-2, Notch 1, and Hes-1 protein expressions increased obviously (P<0.05). Notch signaling pathway inhibitor DAPT reversed the protective effect of edaravone on myocardial injury in rats with CHF (P<0.05).   Conclusion Edaravone may improve myocardial injury in CHF rats by activating Notch/Hes- 1 signaling pathway.