Kruppel样因子14调节Chemerin/CMKLR1通路在心梗后心室重构中的作用及其分子机制

The recent discovered adipocytokine chemerin is closely associated with cardiovascular diseases. Nowadays studies suggest that chemerin plays its roles mainly by binding to its receptor CMKLR1 in mammalian cells, and its expression may be regulated by Kruppel-like factor 14, which is now considered as the key factor regulating the genes in adipocytes. Our earlier study demonstrated that serum chemerin levels significantly increased in chronic heart failure patients. And expression of chemerin is upregulated in the rat fibroblasts stimulated by angiotension II. Silence of chemerin gene by siRNA method promoted proliferation of AngII treatment cardiac fibroblasts. According to these results, we hypothesis that KLF14 regulated the expression of chemerin, leading to the alteration of chemerin/CMKLR1 pathway activities, and followed by the modification of downstream signal pathway such as ERK1/2. This means KLF14-chemerin/CMKLR1 pathway plays an important role in cardiac remodeling. In this study, we will focus on the effect of this KLF14-chemerin/CMKLR1 pathway and tentativly explore the possible molecular mechanism in cardiac remodeling after heart infarction. We hope the results will provide us the new therapeutic target to the cardiac remodeling.

晚近发现的脂肪因子chemerin与心血管疾病密切相关。目前研究显示其在哺乳动物中主要通过其受体CMKLR1发挥作用，其表达可能受脂肪细胞内基因的"总开关"KLF14因子调控。我们的前期研究结果显示，不仅心衰患者血清chemerin水平升高，而且血管紧张素II刺激大鼠心脏成纤维细胞亦可上调chemerin表达；沉默chemerin基因促进AngII刺激的成纤维细胞增殖反应。根据这些结果，我们假设在心梗后心室重构中，KLF14调控chemerin表达，而chemerin/CMKLR1的活化可能产生下游效应，如ERK1/2信号途径活性的改变，起到保护心肌作用。由此我们拟在整体动物和细胞分子水平展开研究，明确心室重构中KLF14、chemerin及受体表达变化，以及KLF14对chemerin/CMKLR1的调节作用及其下游功效，初步探索可能的分子机制，为心力衰竭的防治提供新的理论基础和思路。

晚近发现的脂肪因子chemerin与心血管疾病密切相关。目前研究显示其在哺乳动物中主要通过其受体CMKLR1发挥作用，其表达可能受脂肪细胞内基因的"总开关"KLF14因子调控。本项目研究发现，在心肌细胞肥大过程中，KLF14和chemerin表达水平上调。siRNA抑制chemerin表达后心肌细胞受AngII刺激肥大程度减轻，说明chemerin促进心肌细胞肥大；而KLF14慢病毒感染心肌细胞后上调KLF14表达水平，可加重ISO诱导的心肌细胞肥大和AngII诱导的心脏成纤维细胞增生，说明KLF14亦可促进心室重构过程。在动物模型上，心室重构心脏组织中，免疫组织化学染色显示KLF14和chemerin表达水平升高，与细胞实验结果一致。心肌内注射KLF14慢病毒上调其表达后，可加重心肌肥厚，同时，KLF14在心脏组织的上调，也导致了chemerin表达水平的上升。说明KLF14通过chemerin途径影响心室重构。这一结果初步揭示了新的调节心室重构的信号通路和分子机制，为心力衰竭的防治初步提供了新的理论基础和思路。