LncRNA MALAT1 regulates diabetic cardiac fibroblasts through the Hippo-YAP signaling pathway
LncRNA MALAT1 regulates diabetic cardiac fibroblasts through the Hippo-YAP signaling pathway
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LncRNA MALAT1通过Hippo-YAP信号通路调控糖尿病心脏成纤维细胞
DOI：
10.1139/bcb-2019-0434
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发表时间：
2020-10-01
影响因子：
2.9
通讯作者：
Zhan, Xiaorong
中科院分区：
文献类型：
--
作者：
Liu, Jiangwen;Xu, Liang;Zhan, Xiaorong
糖尿病心肌病（DCM）是一种主要的糖尿病相关微血管疾病。LncRNA MALAT 1在响应缺氧和高水平葡萄糖（高糖）的心肌细胞中广泛表达。在这项研究中，心脏成纤维细胞（CF）转染si-MALAT 1和暴露于高葡萄糖。高糖组给予30 mmol/L葡萄糖，对照组给予5.5 mmol/L葡萄糖。检测MALAT 1在CFs细胞核和细胞质中的表达。检测CFs的生物学行为、胶原生成、Hippo-雅普通路的活性以及雅普的核定位。建立扩张型心肌病小鼠模型，观察心肌组织病理变化，并测定I型胶原、Bax、Bcl-2的表达。分析MALAT 1与雅普之间的相互作用，检测高糖处理的CFs中CREB的表达。MALAT 1在高糖CFs中表达上调，位于细胞核。高糖可增加胶原蛋白的生成、炎症反应、细胞增殖、细胞侵袭力以及MST 1和LATS 1的磷酸化，还可促进雅普的核转位。在高糖处理的CF和DCM小鼠中的这些趋势通过用si-MALAT 1转染而逆转。MALAT 1通过与CREB结合，正调控雅普的核转位。CREB水平在高糖CF中增加，但在沉默MALAT 1后下降。这些结果表明si-MALAT 1通过Hippo-YAP途径和CREB减少高糖CF和DCM小鼠中的炎症和胶原积累。
Diabetic cardiomyopathy (DCM) is a major diabetes-related microvascular disease. LncRNA MALAT1 is widely expressed in cardiomyocytes responding to hypoxia and high levels of glucose (high glucose). In this study, cardiac fibroblasts (CFs) were transfected with si-MALAT1 and exposed to high glucose. CFs in the high glucose groups were treated with 30 mmol/L glucose, and the control CFs were treated with 5.5 mmol/L glucose. The expression of MALAT1 in the nucleus and cytoplasm of CFs was detected. The biological behavior of CFs, as well as collagen production, activity of the Hippo-YAP pathway, and nuclear localization of YAP were measured. Mouse models of DCM were established to observe the pathological changes to myocardium and determine the levels of collagen I, Bax, and Bcl-2. The interaction between MALAT1 and YAP was analyzed, and CREB expression in the high-glucose treated CFs was detected. MALAT1 was upregulated in high-glucose CFs and located in the nucleus. High-glucose increased collagen production, inflammation, cell proliferation, cell invasiveness, and phosphorylation of MST1 and LATS1, and also promoted nuclear translocation of YAP. These trends in high-glucose treated CFs and the DCM mice were reversed by transfection with si-MALAT1. MALAT1 positively regulated the nuclear translocation of YAP by binding to CREB. CREB levels were increased in the high-glucose CFs, but decreased after silencing MALAT1. These results indicate that si-MALAT1 reduces inflammation and collagen accumulation in high-glucose CFs and DCM mice via the Hippo-YAP pathway and CREB.