气体信号分子SO_(2)通过PI3K/AKT1激活自噬改善甲亢大鼠心肌纤维化  

The gas signaling molecule SO_(2)improves myocardial fibrosis in hyperthyroid rats by activating autophagy through PI3K/AKT1

作　　者：王森 聂连桂 刘达 宋熊 杨军[1] WANG Sen;NIE Lian-Gui;LIU Da(Department of Cardiovascular Medicine,the First Affiliated Hospital of South China University,Hengyang 421000,Hunan,China)

机构地区：[1]南华大学附属第一医院心血管内科,湖南衡阳421000

出　　处：《中国老年学杂志》2023年第23期5776-5780,共5页Chinese Journal of Gerontology

基　　金：国家自然科学基金面上项目(81870230);湖南省自然科学基金项目(2019JJ80033,2021JJ40499);湖南省卫生健康科研计划课题项目(B2019121);湖南省自然科学基金科卫联合课题(2021JJ70035)。

摘　　要：目的探讨气体信号分子二氧化硫(SO_(2))通过下调磷脂酰肌醇3激酶/蛋白激酶B(PI3K/AKT)激活细胞自噬改善甲状腺功能亢进(甲亢)大鼠心肌纤维化的作用和机制。方法取40只成年雄性SD大鼠随机均分为4组:对照组,甲亢模型〔左旋甲状腺素(L-Thy)〕组,SO_(2)干预(L-Thy+SO_(2))组,HDX干预(L-Thy+SO_(2)+HDX)组,以连续5 w腹腔注射L-Thy(250μg/ml,2 ml/100 g)构建甲亢大鼠模型,将SO_(2)供体硫酸钠(Na_(2)SO_(3))/硫酸氢钠(NaHSO_(3))以85 mg/(kg·d)分别给予L-Thy+SO_(2)组和L-Thy+SO_(2)+HDX组腹腔注射,L-Thy+SO_(2)+HDX组另予天冬氨酸异羟戊酸(HDX)25 mg/(kg·w)腹腔注射,干预后以酶联免疫吸附试验(ELISA)检测心肌组织中SO_(2)含量,并以Masson染色法检测胶原纤维沉积,Western印迹法检测PI3K/AKT1及自噬相关蛋白ATG5、ATG12和ATG16等表达水平。结果与对照组相比,L-Thy组出现明显心肌纤维化,PI3K/AKT1蛋白表达明显上调,自噬相关蛋白ATG5、ATG12及ATG16表达明显下调(P<0.05),而SO_(2)干预后可改善甲亢大鼠心肌以上变化,HDX则可逆转SO_(2)的干预作用。结论气体信号分子SO_(2)可抑制甲亢大鼠心肌纤维化,其机制可能与下调PI3K/AKT1信号通路激活细胞自噬有关。Objective To investigate the effect and mechanism of gaseous signal molecule sulfur dioxide(SO_(2))on myocardial fibrosis in hyperthyroidism rats by down regulating phosphatidylinositide 3-kinase/protein kinase B(PI3K/AKT)and activating autophagy.Methods Forty adult male SD rats were randomly divided into four groups:control group,hyperthyroidism model〔Levothyroxine(L-Thy)〕group,SO_(2)intervention(L-Thy+SO_(2))group and HDX intervention(L-Thy+SO_(2)+HDX)group.The hyperthyroidism rat model was established by intraperitoneal injection of L-Thy(250μg/ml,2 ml/100 g)for 5 w,the SO_(2)donor sodium sulfate(Na 2SO_(3))/sodium bisulfate(NaHSO_(3))was injected intraperitoneally at 85 mg/(kg·d)into L-Thy+SO_(2)group and L-Thy+SO_(2)+HDX group respectively,and the L-Thy+SO_(2)+HDX group was injected intraperitoneally with L-aspartate-β-hydroxamate(HDX)25 mg/(kg·w).After the intervention,the SO_(2)content in myocardial tissue was detected by enzyme linked immunosorbent assay(ELISA),and the deposition of collagen fibers was detected by Masson staining.The expression levels of PI3K/AKT1 and autophagy related proteins ATG5,ATG12 and ATG16 were detected by Western blotting.Results Compared with the control group,L-Thy group had obvious myocardial fibrosis,the expressions of PI3K/AKT1 protein were significantly up-regulated,and the expressions of autophagy related protein ATG5,ATG12 and ATG16 were significantly down-regulated(P<0.05).After SO_(2)intervention,the above changes of myocardium in hyperthyroidism rats were improved,and HDX reversed the intervention effect of SO_(2).Conclusions Gaseous signal molecule SO_(2)could inhibit myocardial fibrosis in hyperthyroidism rats,and its mechanism might be related to the activation of cell autophagy by down regulating PI3K/AKT1 signal pathway.

关 键 词：二氧化硫 甲状腺素 心肌重构 磷脂酰肌醇3激酶/蛋白激酶B(PI3K/AKT) 自噬 

分 类 号：R58[医药卫生—内分泌]