Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, School of Basic Medicine, Henan University, Kaifeng, China.
Department of General Pathology, Huaihe Hospital, Henan University, Kaifeng, China.
J Cell Mol Med. 2018 Sep;22(9):4437-4448. doi: 10.1111/jcmm.13743. Epub 2018 Jul 11.
NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti-hyperglycaemia and anti-inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL-1β and IL-18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down-regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C-reactive proteins (CRPs), IL-1β and IL-18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS-mediated NLRP3 inflammasome activation.
NLRP3 炎性小体的激活在糖尿病心肌病 (DCM) 中起着重要作用，这可能与活性氧 (ROS) 的过度产生有关。绞股蓝皂苷（Gps）是绞股蓝（Thunb.）Makino 的主要成分，具有降血糖和抗炎作用，但 Gps 是否改善心肌损伤及其机制尚不清楚。在这里，我们发现高葡萄糖 (HG) 通过激活 NLRP3 炎性小体，然后促进 H9C2 细胞和 NRVMs 中 IL-1β 和 IL-18 的分泌，从而导致心肌损伤。同时，HG 增加了 ROS 的产生，这对 NLRP3 炎性小体的激活至关重要。此外，ROS 通过细胞色素 c 流入细胞质并与 NLRP3 结合来主要激活 NLRP3 炎性小体。ROS 和细胞色素 c 的抑制显著下调了由 HG 诱导的 NLRP3 炎性小体的激活，并改善了由 HG 诱导的心肌细胞损伤，这在用 Gps 处理的细胞中也得到了检测。此外，Gps 还降低了 C 反应蛋白 (CRPs)、IL-1β 和 IL-18 的水平，抑制了 NLRP3 炎性小体的激活，从而在体内改善了心肌损伤。这些发现提供了一种机制，即 HG 诱导的 ROS 通过细胞色素 c 与 NLRP3 结合激活 NLRP3 炎性小体，而 Gps 可能通过抑制 ROS 介导的 NLRP3 炎性小体激活成为治疗 DCM 的潜在有效药物。
