调节单核/巨噬细胞自噬抑制急性心肌梗死后心肌过度纤维化的研究

Excessive fibrosis contributes to ventricular remodeling after acute myocardial infarction(AMI). Monocytes/Macrophages play a key role in cardiac fibrosis post AMI through mediating and augmenting inflammation, promoting fibroblast activation and enhancing monocyte-to-myofibroblast transition (MMT). Our initial research found upregulation of autophagy of monocytes/macrophages could 1) downregulated their pro-inflammatory cytokines’ expression; 2)decreased the secretion of TGF-β which is the most important cytokine deeply involved in fibrosis; 3) reduced the level of phosphorylated Smad3, one of the key proteins in TGF-β/Smad3 signaling which mediates MMT, in monocytes/macrophages post TGF-β1 stimulation. Therefore, we hypothesized that regulation of autophagy in monocytes/macrophages could alleviate the excessively fibrotic repairation post AMI and alleviate cardiac remodeling basing on the following mechanisms: 1) by attenuating inflammation post AMI to alleviate cardiomyocyte injury; 2) by reducing secretion of TGF-β to prevent excessive activation of fibroblast; 3) by inhibiting TGF-β/Smad3 pathway to reduce MMT. We will carry out in vitro (cell experiments) and in vivo (murine AMI model) to verify the hypothesis. Through this project we will reveal a novel role of monocytes/macrophages and their autophagy in cardiac repair and demonstrate a new target for anti-fibrotic therapy post AMI.

过度纤维化是急性心肌梗死（AMI）后心室重构的重要机制，单核/巨噬细胞通过介导炎症扩大、促进成纤维细胞激活及自身向肌成纤维细胞转化全程参与了AMI后纤维化过程。我们前期研究发现，增强单核/巨噬细胞自噬可下调其促炎因子表达，减少促纤维化因子TGF-β表达，并降低促其向肌成纤维细胞转化的关键信号蛋白Smad3的磷酸化水平。我们据此提出假说：调节单核/巨噬细胞自噬可通过如下机制抑制AMI后心肌过度纤维化，从而缓解心室病理性重构：① 下调AMI炎症强度，减轻炎症扩散及心肌损伤；② 通过下调TGF-β分泌从而抑制成纤维细胞过度激活；③ 通过干扰TGF-β/Smad3通路抑制单核/巨噬细胞向肌成纤维细胞转化。我们拟应用体外细胞实验及体内小鼠心肌梗死后纤维化模型验证此假说，并进一步揭示单核/巨噬细胞及其自噬活动在AMI修复中的作用和机制，为防治AMI后心肌过度纤维化、改善心肌重构提供新的治疗靶点。

抑制心肌梗死后心肌的过度纤维化，是减轻心肌梗死心室重构的关键靶点，单核巨噬细胞参与了心肌梗死后心肌纤维化和心室重构的全过程，但单核巨噬细胞的自噬参与何种作用尚未阐明。本研究发现了：1）体外上调单核巨噬细胞的自噬下调LPS诱导的巨噬细胞炎性因子的表达，上调IL-4诱导的巨噬细胞抗炎因子的表达，从而促进巨噬细胞向M2型转化；2）体外提高单核/巨噬细胞自噬水平可下调TGFβ的表达；3）巨噬细胞自噬水平的提高可能通过抑制TGFβ/Smad信号通路来抑减少TGFβ的表达；4）体内增强单核/巨噬细胞自噬，减轻急性心肌梗死后心肌纤维化，改善心功能。通过本研究我们进一步揭示单核/巨噬细胞及其自噬活动在急性心肌梗死后心肌修复中的作用和机制，为防治急性心肌梗死后心肌过度纤维化、改善心肌重构提供新思路。