Abstract：
Our previous study has indicated that tetrandrine (TET) can target miR-202-5p to repress the activation of transient receptor potential vanilloid type 2 (TRPV2), eventually ameliorating the progression of myocardial ischemia/reperfusion injury (MI/RI). This study is aimed to further ascertain the detailed mechanisms between TET and TRPV2 in MI/RI pathogenesis. Here, a myocardial I/R injury rat model and a hypoxia-reoxygenation (H/R) model in rat myocardial cell line (H9C2 cells) were established. We reported that pronounced upregulation of TRPV2 was observed in I/R rats and H/R-induced H9C2 cells. Silencing of TRPV2 could improve cardiac function and myocardial injury, reduced infarction size, and promoted cardiomyocyte proliferation in I/R rats. In I/R rats or H/R-induced H9C2 cells, cardiomyocyte apoptosis was inhibited by knocking-down TRPV2. Meanwhile, the silenced TRPV2 or TET treatment ameliorated the damaged mitochondrial structure, mitigated ROS generation, restored the impaired ΔΨM, inhibited mPTP opening and alleviated Ca2+ overload in H/R-induced H9C2 cells. The results obtained from the overexpression of TRPV2 were contrary to those depicted above. Moreover, TET could downregulate TRPV2 expression, while the overexpression of TRPV2 could reverse the above protective effects of TET in H/R-induced H9C2 cells. The results indicated that TET may function as a TRPV2 blocking agent, thereby attenuating the progression of MI/RI through modulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function. These findings offer a theoretical foundation for potential clinical application of TET therapy in patients with MI/RI.
摘要：
我们先前的研究表明粉防己碱（TET）可以靶向miR-202-5p来抑制瞬时受体电位香草酸2型（TRPV2）的激活，最终改善心肌缺血/再灌注损伤（MI/RI）的进展。本研究旨在进一步明确TET和TRPV2在MI/RI发病中的作用机制。这里,建立大鼠心肌I/R损伤模型和大鼠心肌细胞系（H9C2细胞）缺氧复氧（H/R）模型。我们报道在I/R大鼠和H/R诱导的H9C2细胞中观察到TRPV2的明显上调。沉默TRPV2可改善心功能和心肌损伤,梗死面积减小，促进I/R大鼠心肌细胞增殖。在I/R大鼠或H/R诱导的H9C2细胞中，敲低TRPV2抑制心肌细胞凋亡。同时,沉默的TRPV2或TET治疗改善了受损的线粒体结构，缓解ROS的产生，恢复受损的ΔkW,抑制H/R诱导的H9C2细胞mPTP开放并减轻Ca2+过载。从TRPV2的过表达获得的结果与上面描述的那些相反。此外，TET可以下调TRPV2的表达，TRPV2的过表达可以逆转TET对H/R诱导的H9C2细胞的上述保护作用。结果表明，TET可以作为TRPV2阻断剂，从而通过调节心肌细胞凋亡来减弱MI/RI的进展，钙稳态和线粒体功能。这些发现为TET治疗MI/RI患者的潜在临床应用提供了理论基础。
