MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin.
MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin.
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MiR-21 通过靶向凝溶胶蛋白预防糖尿病心肌病引起的舒张功能障碍
DOI：
10.1186/s12933-018-0767-z
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发表时间：
2018-09-04
影响因子：
9.3
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Dai B;Li H;Fan J;Zhao Y;Yin Z;Nie X;Wang DW;Chen C
背景糖尿病是世界范围内死亡和发病的主要原因。糖尿病患者中超过50%的死亡是由心血管疾病引起的。心脏舒张功能障碍是糖尿病心肌病的关键早期体征之一，通常发生在收缩功能障碍之前。然而，目前还没有药物被许可用于其treatment.MethodsType 9腺相关病毒联合心肌肌钙蛋白T启动子被用来操纵miR-21在瘦素受体缺陷（db/db）小鼠中的表达。通过超声心动图和血流动力学检查来测量心脏结构和功能。原代心肌细胞和心肌细胞系被用来执行增益/丧失功能的vitro.ResultsWe观察到一个显着减少的miR-21在舒张功能障碍的心脏db/db小鼠。值得注意的是，miR-21的递送有效地防止了心脏舒张功能障碍的早期损害，表现为减少ROS产生，增加生物可利用的NO和减轻db/db小鼠中糖尿病诱导的心肌细胞肥大。通过生物信息学分析和Ago 2免疫共沉淀，我们确定了miR-21直接靶向凝溶胶蛋白，凝溶胶蛋白是肌动蛋白结合蛋白的一个成员，在信号转导中充当转录辅因子。结论miR-21通过靶向gelsolin在糖尿病心肌病中发挥新的作用，为开发基于miR-21的糖尿病心肌病治疗药物提供了分子基础。
BackgroundDiabetes is a leading cause of mortality and morbidity across the world. Over 50% of deaths among diabetic patients are caused by cardiovascular diseases. Cardiac diastolic dysfunction is one of the key early signs of diabetic cardiomyopathy, which often occurs before systolic dysfunction. However, no drug is currently licensed for its treatment.MethodsType 9 adeno-associated virus combined with cardiac Troponin T promoter were employed to manipulate miR-21 expression in the leptin receptor-deficient (db/db) mice. Cardiac structure and functions were measured by echocardiography and hemodynamic examinations. Primary cardiomyocytes and cardiomyocyte cell lines were used to perform gain/loss-of-function assays in vitro.ResultsWe observed a significant reduction of miR-21 in the diastolic dysfunctional heart of db/db mice. Remarkably, delivery of miR-21 efficiently protected against the early impairment in cardiac diastolic dysfunction, represented by decreased ROS production, increased bioavailable NO and relieved diabetes-induced cardiomyocyte hypertrophy in db/db mice. Through bioinformatic analysis and Ago2 co-immunoprecipitation, we identified that miR-21 directly targeted gelsolin, a member of the actin-binding proteins, which acted as a transcriptional cofactor in signal transduction. Moreover, down-regulation of gelsolin by siRNA also attenuated the early phase of diabetic cardiomyopathy.ConclusionOur findings reveal a new role of miR-21 in attenuating diabetic cardiomyopathy by targeting gelsolin, and provide a molecular basis for developing a miRNA-based therapy against diabetic cardiomyopathy.
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影响因子：
7.7
作者：
Huynh K;McMullen JR;Julius TL;Tan JW;Love JE;Cemerlang N;Kiriazis H;Du XJ;Ritchie RH
通讯作者：
Ritchie RH
DOI：
10.4161/cc.28189
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Cheng Z;Almeida FA
通讯作者：
Almeida FA
DOI：
10.1152/ajpendo.2000.279.5.e1104
发表时间：
2000-11-01
影响因子：
5.1
作者：
Belke, DD;Larsen, TS;Severson, DL
通讯作者：
Severson, DL
DOI：
10.1152/ajpheart.00852.2002
发表时间：
2003-07-01
影响因子：
4.8
作者：
Hopkins, TA;Sugden, MC;Lopaschuk, GD
通讯作者：
Lopaschuk, GD
影响因子：
5
作者：
Cheng, Yunhui;Liu, Xiaojun;Zhang, Shuo;Lin, Ying;Yang, Jian;Zhang, Chunxiang
通讯作者：
Zhang, Chunxiang