尼可地尔通过上调核仁素/自噬轴缓解心肌梗死后的心脏重构和功能障碍。
Nicorandil alleviates cardiac remodeling and dysfunction post -infarction by up-regulating the nucleolin/autophagy axis.
机构信息
Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medical Science, Xiangnan University, Chenzhou, Hunan 423000, China.
Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan, China.
出版信息
Cell Signal. 2022 Apr;92:110272. doi: 10.1016/j.cellsig.2022.110272. Epub 2022 Feb 2.
OBJECTIVE
The present study aimed to investigate whether the drug nicorandil can improve cardiac remodeling after myocardial infarction (MI) and the underlying mechanisms.
METHODS
Mouse MI was established by the ligation of the left anterior descending coronary artery and H9C2 cells were cultured to investigate the underlying molecular mechanisms. The degree of myocardial collagen (Col) deposition was evaluated by Masson's staining. The expressions of nucleolin, autophagy and myocardial remodeling-associated genes were measured by Western blotting, qPCR, and immunofluorescence. The apoptosis of myocardial tissue cells and H9C2 cells were detected by TUNEL staining and flow cytometry, respectively. Autophagosomes were observed by transmission electron microscopy.
RESULTS
Treatment with nicorandil mitigated left ventricular enlargement, improved the capacity of myocardial diastolic-contractility, decreased cardiomyocyte apoptosis, and inhibited myocardial fibrosis development post-MI. Nicorandil up-regulated the expression of nucleolin, promoted autophagic flux, and decreased the expressions of TGF-β1 and phosphorylated Smad2/3, while enhanced the expression of BMP-7 and phosphorylated Smad1 in myocardium. Nicorandil decreased apoptosis and promoted autophagic flux in HO-treated H9C2 cells. Autophagy inhibitors 3-methyladenine (3MA) and chloroquine diphosphate salt (CDS) alleviated the effects of nicorandil on apoptosis. Knockdown of nucleolin decreased the effects of nicorandil on apoptosis and nicorandil-promoted autophagic flux of cardiomyocytes treated with HO.
CONCLUSIONS
Treatment with nicorandil alleviated myocardial remodeling post-MI through up-regulating the expression of nucleolin, and subsequently promoting autophagy, followed by regulating TGF-β/Smad signaling pathway.
目的
本研究旨在探讨尼可地尔是否能改善心肌梗死后的心脏重构及其潜在机制。
方法
结扎左前降支冠状动脉建立小鼠心肌梗死模型，培养 H9C2 细胞以研究潜在的分子机制。Masson 染色评估心肌胶原（Col）沉积程度。Western blot、qPCR 和免疫荧光法检测核仁素、自噬和心肌重构相关基因的表达。TUNEL 染色和流式细胞术分别检测心肌组织细胞和 H9C2 细胞的凋亡。透射电镜观察自噬体。
结果
尼可地尔治疗减轻了左心室扩大，改善了心肌舒张-收缩能力，减少了心肌细胞凋亡，抑制了心肌梗死后的纤维化发展。尼可地尔上调核仁素的表达，促进自噬流，降低 TGF-β1 和磷酸化 Smad2/3 的表达，同时增强 BMP-7 和磷酸化 Smad1 在心肌中的表达。尼可地尔减少了 HO 处理的 H9C2 细胞的凋亡和促进自噬流。自噬抑制剂 3-甲基腺嘌呤（3MA）和氯喹二磷酸盐（CDS）减轻了尼可地尔对凋亡的影响。核仁素敲低降低了尼可地尔对凋亡的影响和尼可地尔对 HO 处理的心肌细胞自噬流的促进作用。
结论
尼可地尔通过上调核仁素的表达，随后促进自噬，从而调节 TGF-β/Smad 信号通路，减轻心肌梗死后的心肌重构。
Zotero 插件