Gaseous signalling molecule SO2 via Hippo‑MST pathway to improve myocardial fibrosis of diabetic rats.
Gaseous signalling molecule SO2 via Hippo‑MST pathway to improve myocardial fibrosis of diabetic rats.
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气体信号分子SO2通过河马-MST途径改善糖尿病大鼠的心肌纤维化。
DOI：
10.3892/mmr.2017.7714
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发表时间：
2017-12
影响因子：
3.4
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Liu M;Liu S;Tan W;Tang F;Long J;Li Z;Liang B;Chu C;Yang J
最近的研究表明，心血管系统中存在内源性二氧化硫(SO2)生成系统。本研究旨在探讨气态信号分子SO2通过Hppo-MST信号通路抑制细胞凋亡和内质网应激，改善糖尿病大鼠心肌纤维化的作用及其调控机制。雄性SD大鼠40只，随机分为4组，每组10只：正常对照组、糖尿病大鼠[链脲佐菌素组]、二氧化硫干预组(链脲佐菌素+二氧化硫)和糖尿病L-天冬氨酸-羟基甲酸酯(L-天冬氨酸-羟基甲酸酯)治疗组(链脲佐菌素组)。造模后腹腔注射链脲佐菌素(40 mg/kg)建立糖尿病大鼠模型，链脲佐菌素+二氧化硫组给予Na2SO3/NaHSO3溶液0.54 mmol/kg，HDX组给予HDX溶液(25 mg/kg/周)。共4周后，超声心动图评价大鼠心功能，Masson染色、末端脱氧核苷酸转移酶dUTP缺口末端标记染色和透射电子显微镜观察心肌形态变化。采用双抗体夹心法测定SO2含量。Western印迹分析检测细胞凋亡相关蛋白、ERS和Hppo-MST信号转导通路的表达。与对照组相比，STZ组和HDX组心肌细胞排列紊乱，有明显的心肌纤维化，超声心动图显示心功能下降，心肌组织细胞凋亡明显增加，凋亡相关蛋白B细胞淋巴瘤相关蛋白X、caspase-3、caspase-9表达上调，Bcl-2表达下调。ERS和Hippo-MST通路相关蛋白CHOP、GRP94、MST1和MST2的表达显著上调。相比之下，SO2处理可逆转上述变化。与STZ组相比，HDX组心肌纤维化和细胞凋亡进一步增加，而Bax/Bcl-2、caspase-3、caspase-9、ERS和Hippo-MST通路相关蛋白的表达差异无统计学意义。本研究结果表明，气态信号分子SO2能有效改善糖尿病大鼠心肌纤维化，其机制可能与下调Hippo-MST通路，减少细胞凋亡和ERS有关。
Recent studies have indicated the existence of an endogenous sulfur dioxide (SO2)-generating system in the cardiovascular system. The present study aimed to discuss the function and regulatory mechanism of gaseous signal molecule SO2 in inhibiting apoptosis and endoplasmic reticulum stress (ERS) via the Hippo-MST signaling pathway to improve myocardial fibrosis of diabetic rats. A total of 40 male Sprague-Dawley rats were randomly divided into four groups (10 rats per group): Normal control group (control group), diabetic rats group [streptozotocin (STZ) group], SO2 intervention group (STZ+SO2 group) and diabetes mellitus rats treated with L-Aspartic acid β-hydroxamate (HDX) group (HDX group). Diabetic rats models were established by intra-peritoneal injection of STZ (40 mg/kg) Following model establishment, intra-peritoneal injection of Na2SO3/NaHSO3 solution (0.54 mmol/kg) was administered in the STZ+SO2 group, and HDX solution (25 mg/kg/week) was administered in the HDX group. A total of 4 weeks later, echocardiography was performed to evaluate rats' cardiac function; Masson staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and transmission electron microscopy examinations were performed to observe myocardial morphological changes. ELISA was employed to determine the SO2 content. Western blot analysis was performed to detect the expression of proteins associated with apoptosis, ERS and the Hippo-MST signalling pathway. Compared with the control group, the STZ group and HDX group had a disordered arrangement of myocardial cells with apparent myocardial fibrosis, and echocardiography indicated that the cardiac function was lowered, there was an obvious increase of apoptosis in myocardial tissue, the expression levels of apoptosis-associated protein B-cell lymphoma associated protein X, caspase-3 and caspase-9 were upregulated, and Bcl-2 expression was downregulated. The expression of ERS and Hippo-MST pathway-associated proteins, including CHOP, GRP94, MST1 and MST2, were significantly upregulated. By contrast, these above-mentioned changes were reversed by SO2 treatment. Compared with STZ group, the HDX group had a further increase of myocardial fibrosis and apoptosis, while there were no statistically significant differences in the expression of Bax/Bcl-2, caspase-3, caspase-9 and ERS and Hippo-MST pathway-associated proteins. The results of the present study demonstrated that the gaseous signal molecule SO2 can effectively improve the myocardial fibrosis of diabetic rats, and its mechanism may be associated with reduced apoptosis and ERS by downregulated Hippo-MST pathway.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
DOI：
10.1016/j.bbadis.2014.06.030
发表时间：
2015-02
影响因子：
6.2
作者：
Varga, Zoltan V.;Giricz, Zoltan;Liaudet, Lucas;Hasko, Gyoergy;Ferdinandy, Peter;Pacher, Pal
通讯作者：
Pacher, Pal
影响因子：
7.3
作者：
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通讯作者：
Barrufet, Laura Regue
影响因子：
8.2
作者：
Bugger, Heiko;Abel, E. Dale
通讯作者：
Abel, E. Dale
影响因子：
2.4
作者：
Nerheim, Pamela;Krishnan, Subramaniam C.;Shivkumar, Kalyanam
通讯作者：
Shivkumar, Kalyanam