组蛋白甲基转移酶SETD2通过细胞焦亡调控主动脉夹层的机制研究

主动脉夹层是由多种不良因素导致主动脉壁撕裂的心血管急危重症，以平滑肌细胞丢失和弹力纤维断裂为其主要病理表现。研究证实炎症细胞和炎症因子广泛参与主动脉夹层的病理生理进程。细胞焦亡作为一种炎症反应在其进程中可能发挥重要功能。本项目前期研究发现组蛋白甲基转移酶SETD2基因髓系特异性敲除小鼠可显著降低主动脉夹层的发生率和死亡率，其主动脉壁中细胞焦亡关键分子NLRP3表达显著降低。由此申报者猜想，SETD2可能通过调控NLRP3的转录影响细胞焦亡，最终调节主动脉夹层的进展。本项目拟从时间维度入手明确细胞焦亡在主动脉夹层进展中作用。进一步分离腹腔巨噬细胞，在细胞水平探究SETD2对细胞焦亡的作用及其分子机制。最后通过骨髓移植将SETD2敲除的骨髓细胞给予野生型小鼠观察是否能降低主动脉夹层的发生率从而明确其转化应用价值。本课题以SETD2为切入点，从细胞焦亡和炎症入手，探究其在主动脉夹层中的作用机制。

Aortic Dissection is a life-threatening cardiovascular disease associated with many risk factors, such as hypertension, dyslipidaemia and smoking, resulting in the separation of the layers of the aortic wall. The main pathological changes include the loss of smooth muscle cells and the fragmentation of elastin fibers. Recent research has shown that inflammatory cells and cytokines are involved in the development of aortic dissection. Pyroptosis, a proinflammatory form of regulated cell death, might play a vital role in this disease. Our preliminary study found that the histone methyltransferase SETD2-myeloid-specific conditional deficient mice exhibited the lower morbidity and mortality compared with normal mice when subjected to β-aminopropionitrile (BAPN)-induced aortic dissection. Surprisingly, we found that the expression of NLR Family Pyrin Domain Containing 3 (NLRP3), the key molecule of pyroptosis, was downregulated in the aortic wall of SETD2-myeloid-specific conditional deficient mice. Thus, we hypothesized SETD2 might regulate the transcription of NLRP3 and the progress of pyroptosis, resulting in the aortic dissection. Our current study will further determine the role of pyroptosis in the progress of aortic dissection. Furthermore, we will the separate the mouse peritoneal macrophage and explore the molecular mechanisms that SETD2 regulates pyroptosis and aortic dissection. Finally, bone marrow transplantation will be applied to confirm the translational potential of SETD2 as a therapeutic target in vivo. Our study focuses on the histone methylation modification and provide us with new strategies for pharmacological treatment of aortic dissection.