MiR-135a Protects against Myocardial Injury by Targeting TLR4
MiR-135a Protects against Myocardial Injury by Targeting TLR4
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MiR-135a 通过靶向 TLR4 防止心肌损伤
DOI：
10.1248/cpb.c20-01003
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发表时间：
2021-06-01
影响因子：
1.7
通讯作者：
Zhou, Yafeng
中科院分区：
文献类型：
--
作者：
Feng, Hui;Xie, Bing;Zhou, Yafeng
新出现的证据强调了microRNAs（miRNAs）作为心血管疾病功能调节因子的重要性。本研究旨在探讨miR-135 a在异丙肾上腺素（ISO）刺激后心脏损伤调控中的功能意义及其作用机制。用腺相关病毒表达系统构建心肌特异性过表达miR-135 a的小鼠模型。采用ISO（60 mg/kg/d，连续14 d）诱导大鼠心肌损伤模型。在体外，我们使用H9 c2细胞通过ISO刺激（10 μ M）建立细胞损伤模型。结果表明，miR-135 a在ISO注射的0-6天期间增加，然后在ISO注射的8-14天期间下调。miR-135 a的表达与体内结果一致。此外，心脏过表达miR-135 a的小鼠表现出心脏纤维化、乳酸脱氢酶水平、肌钙蛋白I、炎症反应和细胞凋亡减少。过表达miR-135 a也可改善ISO诱导的心功能不全。miR-135在H9 c2细胞中的过表达增加了细胞活力，降低了细胞凋亡和炎症对ISO的响应。相反，H9 c2细胞中的miR-135沉默降低了细胞活力，并增加了细胞凋亡和炎症对ISO的响应。从机制上讲，我们发现miR-135 a负调控toll样受体4（TLR 4），这是通过荧光素酶测定证实的。此外，TLR 4抑制剂eritoran消除了miR-135沉默的不利影响。总体而言，miR-135 a通过抑制TLR 4途径促进ISO诱导的心脏损伤。miR-135 a可能是心脏损伤的治疗剂。
Emerging evidence highlights the importance of microRNAs (miRNAs) as functional regulators in cardiovascular disease. This study aimed to investigate the functional significance of miR-135a in the regulation of cardiac injury after isoprenaline (ISO) stimulation and the underlying mechanisms of its effects. Murine models with cardiac-specific overexpression of miR-135a were constructed with an adeno-associated virus expression system. The cardiac injury model was induced by ISO injection (60 mg/kg per day for 14 d). In vitro, we used H9c2 cells to establish a cell injury model by ISO stimulation (10 mu M). The results indicated that miR-135a was increased during days 0-6 of ISO injection and was then downregulated during days 8-14 of ISO injection. The expression of miR-135a was consistent with the in vivo findings. Moreover, mice with cardiac overexpression of miR-135a exhibited reduced cardiac fibrosis, lactate dehydrogenase levels, Troponin I, inflammatory response and apoptosis. Overexpression of miR-135a also ameliorated cardiac dysfunction induced by ISO. MiR-135 overexpression in H9c2 cells increased cell viability and decreased cell apoptosis and inflammation in response to ISO. Conversely, miR-135 silencing in H9c2 cells decreased cell viability and increased cell apoptosis and inflammation in response to ISO. Mechanistically, we found that miR-135a negatively regulated toll-like receptor 4 (TLR4), which was confirmed by luciferase assay. Furthermore, the TLR4 inhibitor eritoran abolished the adverse effect of miR-135 silencing. Overall, miR-135a promotes ISO-induced cardiac injury by inhibiting the TLR4 pathway. MiR-135a may be a therapeutic agent for cardiac injury.