CCDC11抑制动脉粥样硬化效应及机制研究

Vasostatin-2 has a significant inhibitory effect on atherosclerosis。 We have recently shown that vasostatin-2 increases a coiled-coil domain-containing protein (CCDC) 11. However, the biological effect of CCDC11 remains unclear. In our previous study, we obtained atherosclerotic vessel and non-atherosclerotic control vessels. The levels of CCDC11 were significantly increased in atherosclerotic tissue and in mononuclear cells from coronary artery disease patients as compared with control tissues and cells, respectively. In experiments, CCDC11 exerted vascular protection, and inhibited inflammation and atherogenesis. The mRNA microarray of endothelial cells showed that CCDC11 up-regulated CYP4B1 and EP3 expression. In endothelial cell with kockdown of CCDC11 by siRNA or CCDC11-KO mice-derived endothelial cells, CCDC11-induced effects were significantly attenuated. After combining data of previous studies and our findings, we speculate that CCDC11 exhibited vascular protective effects via up-regulating these two proteins. In our future study, we will use inhibitors; RNA interference and CCDC11 knock-in and knock-out mice to explore the protective mechanism of CCDC11, with mechanism clarification. Moreover, the induction of CCDC11 by vasostatin-2 will also be analyzed.

我们曾报道Vasostatin-2有抗炎抗动脉粥样硬化效应，后续发现Vasostatin-2显著上调CCDC11蛋白，但CCDC11生物学作用不明。我们前期研究检测到，粥样硬化血管组织和冠心病患者外周血单个核细胞中CCDC11水平显著低于对照组织和细胞。实验中，CCDC11具保护血管舒张，抑制炎症及抗动脉粥样硬化作用。mRNA芯片证实CCDC11能显著上调CYP4B1和EP3表达；以siRNA下调此二者蛋白会削弱CCDC11刺激所产生的保护效应。结合文献提示CCDC11经上调CYP4B1和EP3分别呈现血管保护和炎症抑制效应。后续研究拟利用抑制剂，RNA干扰、腺病毒以及CCDC11敲入和敲除小鼠，在体内体外实验中阐明CCDC11经上调CYP4B1和EP3保护血管功能，抑制炎症和动脉粥样硬化机制，探讨Vasostatin-2调控CCDC11表达机制，为血管病变的预防和治疗提供新的策略。

我们前期研究证实CCDC11可能介导了心血管保护因子VS2对心血管的保护作用，但CCDC11保护心血管的机制未明。本研究在临床层面证实血清CCD11与冠心病发病呈负相关，且随着疾病严重程度增加水平降低。通过构建CCDC11-KI、内皮特异性CCDC11-KO小鼠模型，我们正反证实 CCDC11能改善血管内皮功能，并抑制血管炎症，改善动脉粥样硬化斑块形成。结合芯片以及后续验证实验，我们证实CCDC11能通过上调CYP4B1表达改善内皮功能，并通过上调EP3抑制血管炎症。此外，心肌CCDC11高表达还能够缓解后负荷增加引起的小鼠心脏重构、并改善心脏功能，此效应可能通过激活MAPK通路，诱导心肌细胞肌小节重组进而调控心肌细胞重构有关。本研究从心血管保护因子VS2入手，探讨Vasostatin-2调控CCDC11表达，改善动脉粥样硬化斑块形成，并改善心功能的机制，为血管病变的预防和治疗提供新的策略。