Notch信号调控巨噬细胞极化在心梗后纤维化重塑中的作用及其机制的研究

The inappropriate fibrosis remodeling after myocardial infarction (MI) is the most important factor for chronic heart failure. However, there is still no effective way to prevent or postpone inappropriate fibrosis remodeling. Our previous studies found that blocking the Notch signaling pathway in cardiac macrophages could promote macrophage M2-type polarization and improve cardiac function in fibrosis remodeling phase after MI, and We also initially proved the mechanism that blocking Notch signaling in liver macrophages inhibited liver fibrosis of which the article had been published on "Hepatology" (Its mechanism was as follows: ┤Notch→ CYLD↑┤ NF-κB┤Inflammatory response┤Hepatic stellate cells activation→ Inhibit hepatic fibrosis). Therefore, we hypothesized that the same mechanism occured in the process that blocking the Notch signaling pathway in cardiac macrophages could promote macrophage M2-type polarization and improve cardiac function in fibrosis remodeling phase after MI.Based on previous studies and by building MI model with Knocking out RBP-J mouse that the Notch signaling has been inhibited in macrophage, this issue comprhensive assesses on the role and possible mechanism that RBP-J-mediated Notch signaling in regulating macrophage polarization in fibrosis remodeling following MI. These studies provide a theoretical basis to find the treatment and prevention of chronic heart failure resulting from inappropriate fibrosis after MI, which has potential clinical applications.

心梗后纤维化重塑失衡是引起慢性心衰发生的主要原因。目前尚无好的方法进行防治。巨噬细胞极化与心梗后纤维化重塑密切相关。我们前期研究发现在心梗后纤维化重塑期阻断Notch信号的心脏巨噬细胞向M2型极化后可明显改善心脏功能，同时我们还初步探明阻断Notch信号的肝巨噬细胞拮抗肝纤维化的机制(已在《Hepatology》上发表，其机制为: ┤Notch→CYLD↑┤NF-κB┤炎症反应┤肝星型细胞活化→抑制肝纤维化)，由此我们推测阻断Notch信号的心脏巨噬细胞向M2型极化后可能也是通过此机制拮抗心梗后纤维化重塑失衡进而改善心功能。本课题在前期研究的基础上利用条件性剔除巨噬细胞上RBP-J（即阻断Notch信号）的小鼠构建心梗模型，对Notch信号调控巨噬细胞极化在心梗后纤维化重塑中的作用及其机制进行深入分析，这些研究为防治心梗后纤维化重塑失衡引起慢性心衰提供了理论依据，具有潜在的临床应用价值。

心梗后纤维化重塑失衡是引起慢性心衰发生的主要原因。目前尚无好的方法进行防治。巨噬细胞极化与心梗后纤维化重塑密切相关。我们前期研究发现在心梗后纤维化重塑期阻断Notch信号的心脏巨噬细胞向M2型极化后可明显改善心脏功能，同时我们还初步探明阻断Notch信号的肝巨噬细胞拮抗肝纤维化的机制，由此我们推测阻断Notch信号的心脏巨噬细胞向M2型极化后可能也是通过此机制拮抗心梗后纤维化重塑失衡进而改善心功能。本课题在前期研究的基础上利用条件性剔除巨噬细胞上RBP-J（即阻断Notch信号）的小鼠构建心梗模型，对Notch信号调控巨噬细胞极化在心梗后纤维化重塑中的作用及其机制进行深入分析，发现1.首次发现巨噬细胞中的Notch信号通路与心梗后心脏功能的恢复密切相关。阻断巨噬细胞中的Notch信号通路可以减轻心梗后心脏损伤，抑制纤维化重塑有助于心脏功能的恢复；2.首次发现阻断巨噬细胞中的Notch信号通路可以抑制梗死区域的巨噬细胞向炎症相关M1型极化而对抗炎相关的M2型极化没有影响，并且影响心梗以外其他组织（血液、骨髓及脾脏）中炎症相关单核细胞生成，进而减少炎症相关巨噬细胞的来源；3.在体外实验中证明了阻断巨噬细胞中的Notch信号可抑制P65及P50的表达，促进CYLD上调抑制IκB降解和P65入核，进而使NF-κB信号通路活化受阻，导致炎症因子分泌减少；4.阻断巨噬细胞中的Notch信号可以促进抗炎相关因子IL-10分泌，提示体外阻断巨噬细胞中的Notch信号可抑制其向M1型极化，促进巨噬细胞向M2型极化；5.抑制纤维化可以预防慢性心衰相关房颤；6.舒芬太尼可改善慢性心衰患者CABG术后的心脏功能；7. 低温通过lncRNA-UIHTC保护心脏免受缺血再灌注损伤；8.白藜芦醇苷通过Notch1 / Hes1介导的Pten / Akt信号激活保护慢性心衰糖尿病患者免受缺血再灌注损伤。这些研究为防治心梗后纤维化重塑失衡引起慢性心衰提供了理论依据，具有潜在的临床应用价值。