Department of Cardiology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China.
Eur Rev Med Pharmacol Sci. 2020 Feb;24(4):2028-2036. doi: 10.26355/eurrev_202002_20381.
To explore the role of imatinib in desoxycorticosterone acetate (DOCA)-induced myocardial fibrosis in rats by the p38 mitogen-activated protein kinase (MAPK) signaling pathway.
Normal group (n=20), DOCA induction group (n=20), and imatinib treatment group (treatment group, n=20) were set up. Then, the cardiac function was examined via magnetic resonance imaging (MRI) and echocardiography (ECG) on the 21st d after modeling. Alkaline phosphatase (ALP) and myocardial function index creatine kinase-MB (CK-MB) were detected. The enzyme-linked immunosorbent assay (ELISA) was performed to measure tumor necrosis factor-gamma (TNF-γ) and interleukin-6 (IL-6). Hematoxylin-eosin (HE) staining assay was carried out to observe the pathological changes in myocardial tissues. Quantitative Polymerase Chain Reaction (qPCR) and Western blotting were employed to measure the expression levels of important myocardial fibrosis-related genes [checkpoint kinase 1 (Chek1) and alpha-smooth muscle actin (α-SMA)], as well as genes and proteins of the p38 MAPK signaling pathway.
In comparison with the normal group, DOCA induction group had significantly lowered fractional shortening (FS, %) and ejection fraction (EF, %), but overtly increased left ventricular end-diastolic dimension (LVEDd) and left ventricular end-systolic dimension (LVESd), as well as levels of serum ALP, alanine aminotransferase (ALT), and CK-MB. Besides, the levels of TNF-γ, IL-6, and IL-1β were notably raised in the DOCA induction group. HE staining results showed that myocardial injury was more severe in DOCA induction group. The results of the gene detection revealed that the expression levels of Chek1, α-SMA, p38 MAPK, and JNK were evidently higher in DOCA induction group than those in the imatinib treatment group (p<0.05), and the expression of p38 MAPK protein in the rat myocardial tissues was remarkably lower in the treatment group than that in the DOCA induction group (p<0.05).
Imatinib can regulate the repair of myocardial injury caused by DOCA-induced myocardial fibrosis in rats by repressing the p38 MAPK signaling pathway.
通过 p38 丝裂原活化蛋白激酶（MAPK）信号通路探讨伊马替尼在醛固酮（DOCA）诱导的大鼠心肌纤维化中的作用。
建立正常组（n=20）、DOCA 诱导组（n=20）和伊马替尼治疗组（治疗组，n=20）。建模后第 21 天，通过磁共振成像（MRI）和超声心动图（ECG）检查心功能。检测碱性磷酸酶（ALP）和心肌功能指标肌酸激酶同工酶-MB（CK-MB）。采用酶联免疫吸附试验（ELISA）检测肿瘤坏死因子-γ（TNF-γ）和白细胞介素-6（IL-6）。进行苏木精-伊红（HE）染色观察心肌组织的病理变化。采用定量聚合酶链反应（qPCR）和 Western blot 检测重要心肌纤维化相关基因[检查点激酶 1（Chek1）和α-平滑肌肌动蛋白（α-SMA）]以及 p38 MAPK 信号通路的基因和蛋白表达水平。
与正常组相比，DOCA 诱导组的射血分数（EF，%）和短轴缩短率（FS，%）明显降低，但左心室舒张末期内径（LVEDd）和左心室收缩末期内径（LVESd）明显增加，血清 ALP、丙氨酸氨基转移酶（ALT）和 CK-MB 水平也明显升高。此外，DOCA 诱导组的 TNF-γ、IL-6 和 IL-1β 水平明显升高。HE 染色结果显示，DOCA 诱导组心肌损伤更严重。基因检测结果表明，DOCA 诱导组 Chek1、α-SMA、p38 MAPK 和 JNK 的表达水平明显高于治疗组（p<0.05），治疗组大鼠心肌组织中 p38 MAPK 蛋白的表达明显低于 DOCA 诱导组（p<0.05）。
伊马替尼通过抑制 p38 MAPK 信号通路，调节 DOCA 诱导的大鼠心肌纤维化引起的心肌损伤修复。
