Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial-mesenchymal transition in the valvular damage due to rheumatic heart disease
Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial-mesenchymal transition in the valvular damage due to rheumatic heart disease
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DOI：
10.3892/mmr.2020.11648
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发表时间：
2021-01-01
影响因子：
3.4
通讯作者：
Zeng, Zhiyu
中科院分区：
文献类型：
--
作者：
Xian, Shenglin;Chen, Ang;Zeng, Zhiyu
风湿性心脏病（RHD）是由A组溶血性链球菌感染后的风湿热引起的自身免疫性疾病，主要影响二尖瓣。风湿性心脏病目前是一个主要的全球性健康问题。然而，与RHD引起的心脏瓣膜损伤相关的确切病理机制仍有待阐明。内皮-间充质转化（endMT）在许多疾病中起关键作用，在心脏纤维化中起重要作用，激活素/Smad2和3信号通路参与调节EndMT。然而，据作者所知，迄今为止还没有研究调查RHD和EndMT之间的关联。因此，本研究的目的是研究EndMT在心脏瓣膜损伤中的潜在作用，并评估在灭活A组链球菌和完全弗氏佐剂诱导的RHD大鼠模型中，激活素/Smad2和3信号传导是否在RHD诱导的瓣膜损伤期间被激活。通过苏木精-伊红和天狼星红染色评估炎症和纤维化。用ELISA试剂盒测定血清细胞因子和类风湿因子水平。激活素/Smad2和3信号通路相关因子[激活素A、Smad2、Smad3、磷酸化（p-）Smad2和p-Smad3]、EndMT相关因子[淋巴增强因子-1（LEF-1）、Snail 1、TWIST、锌指E盒结合同源盒（ZEB）1、ZEB 2、α平滑肌肌动蛋白使用逆转录定量PCR和蛋白质印迹分析检测了血管紧张素转换酶（α-SMA）和I型胶原α 1（COL1A1）]、血管紧张素转换酶相关标志物（BAX和裂解的半胱天冬酶-3）和瓣膜炎症标志物（NF-κ B和p-NF-κ B）。与对照组相比，治疗组的瓣膜炎症和纤维化程度、血清IL-6、IL-17、TNF-α水平及瓣膜病变相关标志物的表达（BAX和切割的半胱天冬酶-3）和瓣膜炎症标志物（p-NF-κ B）、激活素/Smad2和3信号通路相关因子RHD组中（激活素A、p-Smad 2和p-Smad 3）、EndMT相关因子（LEF-1、Snail 1、TWIST、ZEB 1、ZEB 2、alpha-SMA和COL 1A 1）显着增加。提示激活素/Smad2和3信号通路在RHD所致心脏瓣膜损伤的发生发展过程中被激活，EndMT参与了RHD所致心脏瓣膜损伤的发生发展过程。
Rheumatic heart disease (RHD) is an autoimmune disease caused by rheumatic fever following group A hemolytic streptococcal infection and primarily affects the mitral valve. RHD is currently a major global health problem. However, the exact pathological mechanisms associated with RHD-induced cardiac valve damage remain to be elucidated. The endothelial-mesenchymal transition (EndMT) serves a key role in a number of diseases with an important role in cardiac fibrosis and the activin/Smad2 and 3 signaling pathway is involved in regulating the EndMT. Nevertheless, there are no studies to date, to the best of the authors' knowledge, investigating the association between RHD and EndMT. Thus, the aim of the current study was to investigate the potential role of EndMT in cardiac valve damage and assess whether activin/Smad2 and 3 signaling was activated during RHD-induced valvular injury in a rat model of RHD induced by inactivated Group A streptococci and complete Freund's adjuvant. Inflammation and fibrosis were assessed by hematoxylin and eosin and Sirius red staining. Serum cytokine and rheumatoid factor levels were measured using ELISA kits. Expression levels of activin/Smad2 and 3 signaling pathway-related factors [activin A, Smad2, Smad3, phosphorylated (p-)Smad2 and p-Smad3], EndMT-related factors [lymphoid enhancer factor-1 (LEF-1), Snail1, TWIST, zinc finger E-box-binding homeobox (ZEB)1, ZEB2, alpha smooth muscle actin (alpha -SMA) and type I collagen alpha 1 (COL1A1)], apoptosis-related markers (BAX and cleaved caspase-3) and valvular inflammation markers (NF-kappa B and p-NF-kappa B) were detected using reverse transcription-quantitative PCR and western blot analyses. Compared with the control group, the degree of valvular inflammation and fibrosis, serum levels of IL-6, IL-17, TNF-alpha and expression of apoptosis-related markers (BAX and cleaved caspase-3) and valvular inflammation marker (p-NF-kappa B), activin/Smad2 and 3 signaling pathway-related factors (activin A, p-Smad2 and p-Smad3), EndMT-related factors (LEF-1, Snail1, TWIST, ZEB 1, ZEB2, alpha -SMA and COL1A1) were significantly increased in the RHD group. These results suggested that the activin/Smad2 and 3 signaling pathway was activated during the development of valvular damage caused by RHD and that the EndMT is involved in RHD-induced cardiac valve damage.