CXCL10/CXCR3轴介导早期炎症反应在心肌梗死过程中的调控作用与机制

Myocardial infarction (MI) is the one of main diseases threating people's health. At present, no effective therapies are available for MI. Recent studies suggested that the expression of chemokine CXCL10 was significantly increased during MI. However, the role of CXCL10 in MI remains unclear. Our previous studies have revealed that: ①transcription factor NF-kB significantly contributes to expression of CXCL10 in inflammatory cells; ②the expression of CXCL10 and activation of NF-kB is increased during ischaemia of cardiac microvascular endothelial cells; ③the infiltration of inflammatory cells into infarcted myocardium markedly increases. Based on above results, we hypothesize that CXCL10/CXCR3 mediated early inflammatory response plays a key role in pathogenesis of MI, interferation of CXCL10/CXCR3 axis and related regulatory targets will contribute to the repair anf regeneration of infarcted myocardium. In the present projedt, we will firstly explore the relationship between CXCL10 and infiltration phenotype of inflammatory cell and the mechanism for CXCL10 production during MI of SD rat. Secondly, we will examine the effect of CXCL10 on biological function of myocardial cells, cardiac microvascular endothelial cells, and cardiac fibroblasts. Thirdly, interference targeting CXCL10/CXCR3 and related regulatory targets to elucidate the molecular mechanism in which CXCL10/CXCR3 axis mediated inflammatory response regulates the pathogenesis of MI, and explore novel therapies and targets for repair and regeneration of infarcted myocardium.

心肌梗死（MI）是影响我国人口健康的主要疾病之一，目前尚无彻底疗法。最近研究提示：MI早期趋化因子CXCL10表达显著升高，但其功能角色仍然不清。申请者前期发现：①NF-kB对炎症细胞中CXCL10的表达起关键作用；②缺血缺氧导致心脏微血管内皮细胞中CXCL10表达上升及NF-kB活性增强；③梗死心肌中伴有炎症细胞的大量侵润。基于上述发现，我们建立了"CXCL10/CXCR3介导早期炎症反应可能在MI中充当重要角色，靶向干预该信号轴及其调控节点可有效修复梗死心肌"的研究假想。本项目将：探讨大鼠MI中CXCL10与炎症细胞侵润之间的内在联系及其产生的分子机制；同时探索CXCL10对心脏主要构成细胞生物学功能的影响与机制；并靶向干预CXCL10/CXCR3及其调控节点，进而阐明该信号轴介导早期炎症反应在MI及其修复中的调控作用与机理，为功能性再生梗死心肌提供新的理论与靶点。

心肌梗死（MI）是影响我国人口健康的主要疾病之一，目前尚无彻底疗法。最近研究提示：MI 早期趋化因子CXCL10 表达显著升高，但其功能角色仍然不清。申请者前期发现：①NF-kB 对炎症细胞中CXCL10 的表达起关键作用；②缺血缺氧导致心脏微血管内皮细胞中CXCL10 表达上升及NF-kB 活性增强；③梗死心肌中伴有炎症细胞的大量侵润。基于上述发现，我们建立了“CXCL10/CXCR3 介导早期炎症反应可能在MI中充当重要角色，靶向干预该信号轴及其调控节点可有效修复梗死心肌”的研究假想。本项目通过细胞生物学及分子生物学等技术手段，重点进行了如下研究：1）趋化因子CXCL10及其受体CXCR3在梗死心肌中的表达变化规律；2）趋化因子CXCL10通过CXCR3受体调控心脏内皮细胞迁移的分子机制；3）心脏构成细胞在缺血缺氧状态下调控CXCL10基因表达的分子机制。..通过本项目的研究，我们发现：1）心脏组织中存在CXCL10及其受体CXCR3基因的基础性表达，且心肌梗死过程中伴有CXCR3基因的表达升高；2）缺血缺氧条件可能通过激活NFkB信号通路而进一步促进CXCL10基因的启动子活性，并最终导致CXCL10的mRNA及蛋白质的表达水平；3）CXCL10可通过激活p38/FAK信号通路进而促进心脏内皮细胞的迁移。基于本项目的研究结果已经在Experimental and Molecular Pathology、Cytokine等期刊上发表相关科研论文，目前已经发表标注本基金资助的SCI论文7篇。..上述重要理论研究成果为深入理解CXCL10/CXCR3信号通路介导心肌损伤的作用机制及其关键调控靶点奠定了基础，具有重要的科学意义和理论价值。如果后续能进一步对上述研究成果进行转化应用，将有望对缺血性心脏病研究及诊疗领域产生重要的推动作用。