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 µM). 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.

新出现的证据强调了 microRNA (miRNA) 作为心血管疾病功能调节剂的重要性。本研究旨在探讨 miR-135a 在调节异丙肾上腺素 (ISO) 刺激后心脏损伤中的功能意义及其作用的潜在机制。使用腺相关病毒表达系统构建具有 miR-135a 心脏特异性过表达的小鼠模型。心脏损伤模型由 ISO 注射诱导（每天 60 mg/kg，持续 14 天）。在体外，我们使用 H9c2 细胞通过 ISO 刺激 (10 µM) 建立细胞损伤模型。结果表明 miR-135a 在 ISO 注射的第 0-6 天增加，然后在 ISO 注射的第 8-14 天下调。miR-135a 的表达与体内发现。此外，心脏过表达 miR-135a 的小鼠表现出降低的心脏纤维化、乳酸脱氢酶水平、肌钙蛋白 I、炎症反应和细胞凋亡。miR-135a 的过表达也改善了 ISO 诱导的心脏功能障碍。H9c2 细胞中的 MiR-135 过表达增加了细胞活力并减少了响应 ISO 的细胞凋亡和炎症。相反，H9c2 细胞中的 miR-135 沉默会降低细胞活力并增加细胞凋亡和炎症以响应 ISO。从机制上讲，我们发现 miR-135a 负调控 Toll 样受体 4 (TLR4)，荧光素酶测定证实了这一点。此外，TLR4 抑制剂 eritoran 消除了 miR-135 沉默的不利影响。总体而言，miR-135a 通过抑制 TLR4 通路促进 ISO 诱导的心脏损伤。