心梗后心室重构中5-LOX/CysLT2R途径的作用及补阳还五汤调控

Ventricular remodeling is an adverse reaction to the heart causing by multi-pathological factors. It is the key link of inducing heart failure and sudden death after myocardial infarction. Buyang Huanwu Decoction (BYHWD) is the typical prescription of Supplementing Qi and Promoting Blood Circulation. We found the resistant effect of BYHWD on ventricular remodeling after myocardial infarction. Moreover, the gene expression profiling analysis of the ventricular remodeling rat model indicated that 5-Iipoxygenase/cysteinyl leukotrienes receptor 2 (5-LOX/CysLT2R) signal transduction pathway might play an important role, and the inhibition mechanism of BYHWD might be responsible to it. In this study, we would use the rat model of ventricular remodeling, and the technologies of lentivirus, RNA interference, Western-Blot and qPCR, etc. We want to determine the relationship between ventricular remodeling and 5-LOX/CysLT2R signal transduction pathway, and the role of BYHWD in it. Our study may enrich the mechanism of curative effect in Chinese herbal medicine. It is expected to provide the effective drug and the novel therapy targeted genes on ventricular remodeling, as well as the new research idea of related signal transduction pathway in cells.

心室重构是心脏对多种病理刺激产生的不良适应性反应，是心梗后发生心衰、猝死的关键环节。课题组既往研究中发现益气活血代表方补阳还五汤具有良好的抗心梗后心室重构作用。近期我们采用数字基因表达谱分析对心室重构模型大鼠心脏基因表达进行研究发现: 5-脂氧合酶/半胱氨酰白三烯受体2(5-LOX/CysLT2R)信号传导通路可能在心室重构中起重要作用，补阳还五汤抗心室重构的机制可能和抑制5-LOX/CysLT2R 通路有关。本研究拟采用心梗后心室重构大鼠模型以及慢病毒、RNA 干扰、Western-Blot、qPCR 等技术，对5-LOX/CysLT2R 通路在心室重构中的作用及其可能的机制进行研究，并探讨补阳还五汤对5-LOX/CysLT2R调控作用。研究有望为心室重构的胞内信号转导通路研究提供新的思路，并为探索新的治疗靶点及有效药物、丰富中药疗效机理作出贡献。

心梗后心室重构是心梗患者远期发生心源性死亡的最重要的危险因素之一。近年来随着再灌注技术的发展，急性心肌梗死的死亡率逐年降低，而与此同时越来越多的患者正受到心梗后心室重构、心衰的威胁。加强对心梗后心室重构机制的研究，寻找心梗后心室重构及心衰新的治疗靶点，开发有效药物，无疑是一个值得鼓励的方向。本课题组通过大鼠心梗模型及原代心肌细胞培养等体内外实验，运用数字基因表达谱技术、制备过表达5-LOX腺病毒载体及MTT、Hoechst33342/PI双染、ELISA、Western-Blot等实验技术对心梗后心室重构中5-LOX/CysLT2R途径的作用及补阳还五汤调控进行研究。利用数字基因表达谱技术检测补阳还五汤抗心梗后心室重构机制的差异基因表达谱研究发现5-LOX基因在心肌梗死后心室重构大鼠模型组中表达升高，而在补阳还五汤组表达下降，差异具有统计学意义，提示补阳还五汤具有抑制5-LOX途径激活的作用。体外培养原代心肌细胞利用相关研究技术研究发现氧化应激可激活5-LOX 途径，5-LOX 途径的激活可进一步加重心肌细胞凋亡。补阳还五汤及其有效成分芍药苷均能抑制氧化应激诱导的原代心肌细胞凋亡，但是，5-LOX 途径并不是补阳还五汤抗心肌细胞凋亡的唯一途径，而芍药苷主要通过抑制5-LOX 途径从而抗心肌细胞凋亡，芍药苷可能是补阳还五汤通过调控5-LOX 途径从而抗心肌细胞凋亡的主要有效成分。本研究明确了5-LOX/CysLT2R 途径在心梗后心室重构过程中的作用及补阳还五汤对5-LOX/CysLT2R 途径的作用及其机制。为进一步发掘心梗后心室重构的治疗靶点及有效药物，丰富中药治疗的疗效机理，及心梗后心室重构的防治提供了崭新的思路，是一项十分有意义的创新性尝试。