Department of Physiology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, China.
Experimental Center, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, China.
Biomed Res Int. 2020 Oct 20;2020:3039184. doi: 10.1155/2020/3039184. eCollection 2020.
Inflammatory response during myocardial ischemia reperfusion injury (MIRI) is essential for cardiac healing, while excessive inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanism of these uncontrolled inflammatory processes has a significant impact during the MIRI therapy. Here, we found a critical role of ATP-sensitive potassium channels (K) in the inflammatory response of MIRI and its potential mechanism and explored the effects of Panax Notoginseng Saponins (PNS) during this possess. Rats underwent 40 min ischemia by occlusion of the left anterior descending (LAD) coronary artery and 60 min of reperfusion. PNS was treated at the corresponding time point before operation; 5-hydroxydecanoate (5-HD) and glybenclamide (Gly) (or Nicorandil (Nic)) were used as pharmacological blocker (or nonselective opener) of K. Cardiac function and pathomorphology were evaluated and a set of molecular signaling experiments was tested. K current density was measured by patch-clamp. Results revealed that in MIRI, PNS pretreatment restored cardiac function, reduced infarct size, and ameliorated inflammation through K. However, inhibiting K by 5-HD and Gly significantly reversed the effects, including NLRP3 inflammasome and inflammatory mediators IL-6, MPO, TNF-, and MCP-1. Moreover, PNS inhibited the phosphorylation and nuclear translocation of NF-B in I/R myocardium when the K was activated. Importantly, PNS promoted the expression of subunits and activation of K. The study uncovered K served as a new potential mechanism during PNS modulating MIRI-induced inflammation and promoting injured heart recovery. The manipulation of K could be a potential therapeutic approach for MIRI and other inflammatory diseases.
在心肌缺血再灌注损伤（MIRI）期间，炎症反应对于心脏愈合至关重要，而过度的炎症会延长梗塞并促进不良的心脏重构。了解这些不受控制的炎症过程的机制在 MIRI 治疗中具有重要意义。在这里，我们发现三磷酸腺苷敏感性钾通道（K）在 MIRI 的炎症反应中具有关键作用及其潜在机制，并探讨了在这个过程中三七总皂苷（PNS）的作用。大鼠通过结扎左前降支（LAD）冠状动脉进行 40min 缺血，然后再灌注 60min。PNS 在手术前的相应时间点进行治疗；5-羟葵酸（5-HD）和格列本脲（Gly）（或尼可地尔（Nic））被用作 K 的药理学阻滞剂（或非选择性开放剂）。评估心脏功能和病理形态，并进行了一系列分子信号实验。通过膜片钳测量 K 电流密度。结果表明，在 MIRI 中，PNS 预处理通过 K 恢复心脏功能，减少梗塞面积并减轻炎症。然而，通过 5-HD 和 Gly 抑制 K 会显著逆转这些作用，包括 NLRP3 炎性体和炎性介质 IL-6、MPO、TNF-α和 MCP-1。此外，PNS 在激活 K 时抑制 I/R 心肌中 NF-B 的磷酸化和核转位。重要的是，PNS 促进了 K 亚单位的表达和激活。该研究揭示了 K 作为 PNS 调节 MIRI 诱导的炎症和促进受损心脏恢复的新的潜在机制。K 的操纵可能是 MIRI 和其他炎症性疾病的潜在治疗方法。
