FIZZ1/RELMα-MLCK信号通路对易损血管中斑块稳定性及血管功能的影响及机制研究

At present, the stability of vulnerable plaques in blood vessels and abnormal blood vessel function have been widely attention in the acute cardiovascular events. In preliminary study,we first found that hypoxia induces significant high expression of mitotic factor FIZZ1/RELM alpha in arterial atheromatous plaque,and promotes angiogenesis in endothelial cells. At the same time, we discovered that FIZZ1/RELM alpha-CaM-MLCK signaling pathway causes aortic smooth muscle contraction, and may be involved in angiogenesis in vulnerable plaques,vascular contraction and progress of the vulnerable vessels. In this study, we intend to build the model of vulnerable plaques by using FIZZ1 / RELM alpha stimulus, FIZZ1/RELM alpha expressingvector-transduction, andApoE knockout murine carotid artery.We will further use RNA interference technique to suppress FIZZ1/RELM alpha expression in vulnerable blood vessel plaques and interfere its downstream Ca2+-CaM-MLCK signaling in order to determine the effects and mechanisms of FIZZ1/RELMalpha-MLCK signaling pathway on the stability of vulnerable plaques and blood vessel function in vulnerable vessels, which will provide a novel therapeutic target for the treatment of atherosclerosis in vulnerable vessels.

目前，易损血管中斑块稳定性及异常血管功能在导致急性心血管事件中的重要性已受广泛重视，逆转易损血管的进展，成为防治心血管事件的重要内容。本课题组首先发现缺氧诱导有丝分裂因子FIZZ1/RELMα在动脉粥样斑块内显著表达并促进内皮细胞血管生成，同时预实验发现其能通过Ca2+-CaM-MLCK途径引起主动脉平滑肌收缩，推测其可能参与了易损血管粥样斑块内血管新生、血管异常功能的进程。本研究拟进一步利用FIZZ1/RELMα刺激或FIZZ1/RELMα-expressing转染ApoE基因敲除小鼠颈动脉，构建易损血管模型后，运用RNA干扰抑制易损血管斑块内FIZZ1/RELMα分泌，或者干预其下游Ca2+-CaM-MLCK信号通路，明确FIZZ1/RELMα信号通路通过影响易损斑块内血管新生及动脉功能，而对易损血管进程的影响及机制，为抗动脉粥样硬化中易损血管的治疗提供新的靶点及理论依据。

FIZZ1/RELMα是新发现的缺氧诱导有丝分裂因子，在心血管疾病尤其动脉粥样硬化(AS)方面仅为初步研究。我们首先发现FIZZ1/RELMα在AS斑块内显著表达，并强烈促进主动脉内皮细胞血管生成的研究成果，推测其可能也参与斑块内血管新生、血管收缩并影响斑块易损性进展，本课题进一步用FIZZ1/RELMα刺激或FIZZ1/RELMα-expressing转染ApoE基因敲除小鼠颈动脉，构建易损血管模型后，运用RNA干扰抑制易损血管斑块内FIZZ1/RELMα分泌，或者干预其下游Ca2+-CaM-MLCK信号通路，明确FIZZ1/RELMα信号通路通过影响易损斑块内血管新生及动脉功能，同时我们紧跟国际研究热点，进一步深入研究了长链非编码RNA H19及相关信号通路FIZZ1/RELMɑ对动脉粥样硬化的发生、发展及其下游调节信号通路，采用先进的过FISH、CHIP等技术及观察动脉粥样硬化的分子进程，验证以上科学假说。目前共发表论著5篇，其中SCI2篇（其中一篇影响因子5分），北图核心4篇，现在投论著1篇。已培养硕士研究生2名。本研究将为动脉粥样硬化防治提供新的思路和治疗靶点。