College of Acupuncture and Message, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China.
Departement of Cardiovascular, Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China.
J Cell Biochem. 2019 Dec;120(12):19647-19659. doi: 10.1002/jcb.29271. Epub 2019 Jul 11.
Ischemic heart disease (IHD) is the most occurring cardiovascular-associated disease, which is a primary leading cause of cardiac disability and death worldwide. Myocardial ischemia/reperfusion injury (MI/RI) has been linked to IHD-induced cardiomyocytes apoptosis and tissue damage. The clinical studies have indicated that pathophysiologic mechanisms of MI/RI are associated with reactive oxygen species generation, calcium overload, energy metabolism disorder, neutrophil infiltration, and others. However, the genetic mechanism of MI/RI remains unclear. In this study, we successfully established the reproducing abnormal heart observed in rat, of IHD-induced MI/RI post operation. By using these rats, we illustrated that expression of miR-181b-5p was increased not only in both hypoxia/reoxygenation-cultured H9C2 but also heart of myocardial ischemia/reperfusion (MI/R) rat. Suppression of the miR-181b-5p cardiomyocytes apoptosis and rescued myocardial infarction. Additionally, our data indicated that miR-181b-5p negatively regulates the expression of AKT3 and PIK3R3 through directly binding with its 3'-untranslated region. More importantly, suppression of miR-181b-5p protects the cardiomyocytes apoptosis and tissue damage from MI/R via regulation of PIK3R3 and AKT3. Hence, our study indicates that miR-181b-5p is essential for MI/RI via regulation of PI3K/Akt signaling pathway and could be a potential therapeutic target in IHD.
缺血性心脏病（IHD）是最常见的心血管相关疾病，是全球范围内导致心脏残疾和死亡的主要原因。心肌缺血/再灌注损伤（MI/RI）与 IHD 诱导的心肌细胞凋亡和组织损伤有关。临床研究表明，MI/RI 的病理生理机制与活性氧生成、钙超载、能量代谢紊乱、中性粒细胞浸润等有关。然而，MI/RI 的遗传机制尚不清楚。在这项研究中，我们成功地建立了手术后大鼠 IHD 诱导的 MI/RI 中观察到的异常心脏重现模型。通过使用这些大鼠，我们表明 miR-181b-5p 的表达不仅在缺氧/复氧培养的 H9C2 中增加，而且在心肌缺血/再灌注（MI/R）大鼠的心脏中也增加。抑制 miR-181b-5p 可减少心肌细胞凋亡并挽救心肌梗死。此外，我们的数据表明，miR-181b-5p 通过直接与其 3'非翻译区结合，负调控 AKT3 和 PIK3R3 的表达。更重要的是，抑制 miR-181b-5p 通过调节 PIK3R3 和 AKT3 来保护心肌细胞凋亡和组织损伤免受 MI/R 的影响。因此，我们的研究表明，miR-181b-5p 通过调节 PI3K/Akt 信号通路对 MI/RI 至关重要，并且可能成为 IHD 的潜在治疗靶点。
