活性Cur-NO水凝胶通过调控线粒体自噬抗心肌缺血再灌注损伤的研究

Curcumin (Cur) can significantly protect heart from ischemia/reperfusion injury (IRI) with great value of deserving further research and development, while the mechanism of cardioprotection remains to be elucidated. However, Cur is limited in clinical application for its properties of poor water solubility and low bioavailability. Moreover, supplementation of exogenous nitric oxide (NO) is an effective strategy for the treatment of IRI. In our previous studies, a Cur-hydrogel as well as a NO-hydrogel were respectively synthesized with good water solubility and bioavailability, both of which exerted multiple protective effects in cardiovascular diseases. Inhibition DRp1-mediated mitochondrial fission can attenuate IRI by reducing reactive oxygen species (ROS) production and cardiomyocytes autophagy. Cur can protect brain from IRI by inhibiting Drp1-induced mitochondrial autophagy in nerve cells. In this study, we propose to develop an novel Cur-NO hydrogel which could release Cur as well as NO at the same time, and put forward a scientific hypothesis that the Cur-NO hydrogel could synergistically alleviate cardiac IRI by reducing Drp1-mediated mitochondrial autophagy. From in vitro to in vivo studies, Drp1 gene knockout and transgenic mice would be used to confirm this hypothesis, which may provide principle and experimental foundations for the new therapy of heart IRI.

姜黄素（Cur）具有显著抗缺血再灌注损伤（IRI）心脏保护作用，极具开发前景，但作用机制尚未完全阐明，且存在难溶、生物利用度低等缺陷，临床应用受限。补充外源性NO是减少IRI的一个重要措施。我们在前期分别制备了姜黄素水凝胶及NO-水凝胶，可较好地提高姜黄素的水溶性及生物利用度，NO可纳米缓释，提示两者均具有多重心血管保护作用。文献报道NO可通过抑制Drp1减少线粒体自噬而抗心肌IRI；姜黄素可下调Drp1抑制神经细胞线粒体自噬而发挥脑保护作用。结合前期研究，我们现拟发展一种可同时释放姜黄素及NO的活性Cur-NO水凝胶，并提出科学假说：Cur-NO水凝胶通过抑制Drp1减少线粒体自噬抗心肌IRI的新机制。本项目拟采用Drp1基因敲除小鼠，从在体、细胞及分子水平研究证实该假说并阐明Cur-NO水凝胶通过抑制Drp1调控线粒体自噬发挥心脏保护作用，为预防和减少IRI的新方法奠定理论和实验基础。

缺血性心肌病是目前全球致死率最高的疾病之一，虽然临床上开展的各种再灌注治疗均取得了较好的效果，但心肌在迅速恢复血流的同时会出现再灌注损伤，即心肌缺血再灌注损伤（ischemia reperfusion injury, IRI）。本课题按计划完成了具自组装成胶能力的短肽衍生物连接一氧化氮供体和抗氧化剂姜黄素新型水凝胶（Nap-Cur-NO）的构建，且具有较好的药物缓释能力以及生物安全性，能有效减轻心肌IRI。体外研究发现Nap-Cur-NO可在心肌细胞缺氧/复氧过程中增加细胞内一氧化氮水平以及降低ROS水平，从而抑制ROS相关的p38 MAPK/NF-κB信号通路的表达，此外，Nap-Cur-NO还显著抑制了缺氧/复氧损伤引起的自噬和凋亡。体内研究发现，Nap-Cur-NO能减少心梗面积，减轻再灌注后的心肌重构和改善心脏功能。