Liu X, Xu L, Wu J, Zhang Y, Wu C, Zhang X
Department of Ultrasound, First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China.
Department of Critical Care Medicine, First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2022 Jul 20;42(7):1082-1088. doi: 10.12122/j.issn.1673-4254.2022.07.18.
To explore the role of salt-inducible kinase 2 (SIK2) in myocardial ischemia-reperfusion (IR) injury in rats.
Fifteen male SD rats were randomized equally into sham operation group, myocardial IR model group, and SIK2 inhibitor group (in which the rats were treated with intravenous injection of 10 mg/kg bosutinib the left femoral vein 24 h before modeling). Ultrasound was used to detect the cardiac function of the rats, and myocardial pathologies were observed with HE staining. Transmission electron microscopy was used to observe autophagy of myocardial cells, and Western blotting was performed to detect the contents of the autophagy-related proteins SIK2, LC3B, Beclin-1, p62 and the expressions of p-mTOR, mTOR, p-ULK1, and ULK1 in myocardial tissue.
Myocardial IR injury significantly increased the number of autophagosomes (P < 0.05) and the expression of SIK2 protein ( < 0.01) in the myocardial tissues. Treatment with bosutinib before modeling obviously lowered the expression of SIK2 protein ( < 0.01), alleviated myocardial pathologies, and reduced the number of autophagosomes ( < 0.05) in the myocardial tissue. The rats with myocardial IR injury showed obviously lowered LVEF and FS values ( < 0.001), which were significantly improved by bosutinib treatment ( < 0.05); no significant difference was detected in IVSDd or LVPWDd among the 3 groups ( > 0.05). Myocardial IR injury obviously increased the expressions of LC3-II/LC3-I and Beclin-1 proteins and lowered the expression of p62 protein ( < 0.01), and these changes were significantly rescued by bosutinib treatment ( < 0.05). The rat models of myocardial IR injury showed significantly increased expression of p-ULK1 (Ser757) ( < 0.01) and lowered expression of p-mTOR protein ( < 0.0001) in the myocardium, and these changes were obviously reversed by bosutinib ( < 0.01 or 0.05); there was no significant difference in mTOR and ULK1 expressions among the 3 groups ( > 0.05).
SIK2 may promote autophagy through the mTOR/ULK1 signaling pathway, and inhibiting SIK2 can reduce abnormal autophagy and alleviate myocardial IR injury in rats.
探讨盐诱导激酶2（SIK2）在大鼠心肌缺血再灌注（IR）损伤中的作用。
将15只雄性SD大鼠随机均分为假手术组、心肌IR模型组和SIK2抑制剂组（建模前24 h经左股静脉给大鼠静脉注射10 mg/kg博舒替尼）。采用超声检测大鼠心功能，HE染色观察心肌病理变化。透射电镜观察心肌细胞自噬情况，蛋白质免疫印迹法检测心肌组织中自噬相关蛋白SIK2、LC3B、Beclin-1、p62的含量以及p-mTOR、mTOR、p-ULK1和ULK1的表达。
心肌IR损伤显著增加心肌组织中自噬体数量（P < 0.05）和SIK2蛋白表达（< 0.01）。建模前用博舒替尼处理明显降低SIK2蛋白表达（< 0.01），减轻心肌病理变化，减少心肌组织中自噬体数量（< 0.05）。心肌IR损伤大鼠的左室射血分数（LVEF）和左室短轴缩短率（FS）值明显降低（< 0.001），博舒替尼处理后显著改善（< 0.05）；3组间室间隔舒张末期厚度（IVSDd）和左室后壁舒张末期厚度（LVPWDd）差异无统计学意义（> 0.05）。心肌IR损伤明显增加LC3-II/LC3-I和Beclin-1蛋白表达，降低p62蛋白表达（< 0.01），博舒替尼处理显著逆转这些变化（< 0.05）。心肌IR损伤大鼠模型心肌中p-ULK1（Ser757）表达显著增加（< 0.01），p-mTOR蛋白表达降低（< 0.0001），博舒替尼明显逆转这些变化（< 0.01或0.05）；3组间mTOR和ULK1表达差异无统计学意义（> 0.05）。
SIK2可能通过mTOR/ULK1信号通路促进自噬，抑制SIK2可减少异常自噬，减轻大鼠心肌IR损伤。
