Notch信号调控巨噬细胞参与心肌纤维化的作用和机制研究

Cardiac macrophages can exert dual function in the progression and regression of myocardial fibrosis by either promoting or abrogating the excessive deposition of extracellular matrix, which have been proposed as potential targets in combating fibrosis. Recent experimental studies reveal the advanced progression on macrophages heterogeneity that have been presented by the origin of macrophages subsets and macrophages activation and function. However, the detailed molecular mechanisms of regulation on macrophages heterogeneity during myocardial fibrosis are not well understood. Using macrophage-specific RBP-J deficient mice, our previous studies have shown that Notch signaling blockade is required for macrophages to ameliorate hepatic fibrosis by inhibiting NF-κB activation through cylindromatosis (CYLD)(2015, hepatology). Meanwhile, we found that myocardial fibrosis was also ameliorated in myeloid-specific Notch signaling blockade mice, and the number of inflammatory macrophages around injured region was reduced significantly. These results suggested that Notch signaling could regulate the activation of macrophages involved in myocardial fibrosis. In this project, based on Notch, we intend to clarify the molecular and cellular role of heterogeneity of myocardial macrophages in myocardial fibrosis by using several genetic modified mice. Furthermore, we will verify the role of macrophages heterogeneity in patients with myocardial fibrosis by using clinical tissue samples, and try to develop some possible macrophages-based interventional strategies for myocardial fibrosis therapy in near future These studies are expected to uncover the new molecule mechanisms on regulation of macrophages heterogeneity in myocardial fibrosis, and provide new strategies and targets for the treatment of myocardial fibrosis. Therefore, our studies are of important theoretical significance and potential clinical value.

巨噬细胞在心肌纤维化中发挥重要的调控作用，是极具潜力的治疗靶点。近来巨噬细胞来源、活化和功能异质性研究取得突破性进展，但不同来源和活化模式的巨噬细胞在心肌纤维化中作用及调控机制仍不清楚。我们前期利用巨噬细胞特异性Notch信号阻断小鼠结合CCl4诱导纤维化时发现，Notch-CYLD通过抑制NF-κB减轻肝纤维化（2015,Hepatology），同时也发现Notch信号缺失导致心肌纤维化程度减轻，且炎性巨噬细胞减少。提示：Notch信号能调控巨噬细胞参与心肌纤维化进展。本课题拟以Notch信号为切入点，利用多种基因修饰小鼠，结合心梗模型，从分子、细胞、动物和临床标本水平回答不同来源和活化模式的巨噬细胞在心肌纤维化中的作用及其调控的分子机制，并建立基于巨噬细胞的心肌纤维化干预方案。本研究有望揭示巨噬细胞在心肌纤维化中的作用和机制，为心肌纤维化治疗提供新策略，具有重要的理论和实践意义。

心肌纤维化是多种细胞和分子相互作用的结果。细胞外基质和其他非实质细胞则发挥调节心肌细胞的应激、存活和损伤修复等作用。细胞外基质的过度表达和胶原沉积将引发心肌纤维化。心肌纤维化参与高血压、肥厚性心肌病、心力衰竭和心肌梗塞引起的心肌重塑。如果纤维化重塑过度将引发心衰和心脏猝死的风险。目前临床上尚无理想的治疗心肌纤维化的药物，因而，阐明引发心肌纤维化的细胞和分子机制具有重要的理论意义和实践价值。巨噬细胞迁移抑制因子是巨噬细胞、淋巴细胞和免疫细胞中产生的促炎调节因子，广泛存在于包括心肌细胞在内的细胞中。大量证据证实其在烧伤、糖尿病和缺血-再灌注损伤等病理状态下维持心脏稳态的作用。慢性冷应激对人类健康构成重大威胁，表现为冬季特别是不良心血管事件的季节性死亡率最增高。人们往往在到达医院之前就遭受与气候变化相关的心血管死亡。政府间气候变化专门委员会证实，极端寒冷气候下各种疾病的发病率增加。充足的临床和流行病学证据表明，寒冷气候是不良心血管后遗症的重要因素，包括心律失常风险增加，血液粘度和血压升高，心肌功能和血流动力学受到抑制，导致中风、心肌梗死和心力衰竭的患病率增加。我们的研究证实，多种因素导致的心肌重塑对心功能的维持具有重要的调节作用。然而，过度的心肌纤维化导致心功能损伤进一步加剧，线粒体损伤加剧，活性氧生成增加，巨噬细胞及泛素化连接酶可通过调节Notch信号通路，缓解外界损伤导致的心肌过度重塑。即1）Beclin1通过抑制铁死亡及减轻线粒体损伤抵抗低温诱导的心脏重构和收缩功能障碍。2）USP10介导的Notch1激活对T2DM小鼠心肌梗死损伤具有保护作用。3）TRIM72通过STAT3/Notch-1信号通路减轻主动脉缩窄术后心肌纤维化。综上，我们的研究证实，在多种因素导致的心肌重塑中，Notch信号通路作为重要的调节因子，参与心脏重塑的病理过程。可能为防治心肌不良重塑提供指导作用。