整合素CD11b通过介导单核/巨噬细胞黏附和极化促进心脏重构的分子机制

心肌单核/巨噬细胞聚集和极化是引起心脏重构的重要机制之一。黏附分子在单核细胞黏附中发挥重要作用。申请人既往研究证实黏附分子ICAM-1参与高血压和心脏重构的发生。但其受体整合素CD11b在心脏重构中的作用及机制不清楚。前期研究发现血管紧张素II（Ang II）上调心肌CD11b表达；敲除CD11b抑制Ang II诱导的心肌肥厚、纤维化、功能障碍及巨噬细胞M1极化。骨髓移植也证明骨髓CD11b+细胞的作用。但是CD11b调控心脏重构的分子机制仍需深入研究。本课题拟采用Ang II诱导心脏重构模型，在CD11b敲除、骨髓移植、抑制剂和激动剂处理的小鼠及体外细胞中，探讨Ang II上调心肌CD11b表达的分子机制；明确CD11b在心脏重构中的作用；阐明CD11b调控单核细胞黏附和巨噬细胞极化诱导心肌和成纤维细胞活化的分子机制；最后为阐明CD11b调控心脏重构的发病机制及筛选新药靶点提供实验依据。

Myocardial monocytes/macrophages recruitment is one of the important mechanisms of cardiac remodeling. Adhesion molecules play a critical role in the regulation of cell adhesion. Our recent studies demonstrate that adhesion molecule ICAM-1 is involved in the development of cardiac remodeling. However, the role of its receptor integrin CD11b in regulating cardiac remodeling and the underlying mechanisms remain unclear. Our preliminary results suggest that angiotensin II (Ang II) increased myocardial CD11b expression. Knockout of CD11b attenuated Ang II induced cardiac dysfunction, hypertrophy, fibrosis and macrophage M1 polarization. CD11b bone marrow transplanted experiment also confirmed the role of CD11b+ monocytes in cardiac remodeling. However, the mechanism of CD11b in regulating cardiac remodeling remain to be further explored. Here, cardiac remodeling models were induced by Ang II. Using CD11b knockout and bone marrow transplanted mice, wild-type mice treated with neutralizing antibody and agonist and in vitro cells, we will investigate the molecular mechanism of Ang II upregulates myocardial CD11b expression; the role of CD11b on cardiac remodeling; the molecular mechanism that CD11b regulates the adhesion of monocytes and polarization of macrophages and induces cardiomyocyte and fibroblast activation; Finally, we will provide new evidence for elucidating the mechanisms of CD11b in regulating cardiac remodeling and providing new pharmacological target for prevention and treatment of this disease.