Gao Tingwen, Guo Zhenyang, Weng Xinyu, Cui Yikai, Li Peng, Hu Tao, Luo Wei, Dong Zheng, Wei Peng, Cai Yun, Lu Yijing, Gao Rifeng, Li Hua, Zhong Xin, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Department of Cardiology, Rizhao Heart Hospital, Qingdao University, Rizhao, China.
Cell Death Dis. 2024 Dec 18;15(12):916. doi: 10.1038/s41419-024-07282-5.
The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI.
巨噬细胞相关的炎症反应在心肌缺血再灌注损伤（MIRI）中起重要作用。SHEP1（含SH2结构域的Eph受体结合蛋白1）与炎症细胞的黏附和迁移有关。然而，在MIRI期间，SHEP1调节巨噬细胞的作用和分子机制仍不清楚。在此，在与缺氧复氧心肌细胞共培养的巨噬细胞以及损伤早期缺血再灌注损伤的心肌中，SHEP1的表达增加。在MIRI条件下，SHEP1基因敲除巨噬细胞和SHEP1巨噬细胞特异性缺陷小鼠的细胞迁移和炎症也增强，这进一步导致体内心脏损伤和心脏功能恶化。机制上，巨噬细胞衍生的SHEP1通过MAPK途径竞争性结合G3BP1以抑制炎症。此外，给予G3BP1抑制剂可改善MIRI条件下SHEP1巨噬细胞特异性缺陷小鼠的心脏功能。我们的结果表明，巨噬细胞中SHEP1的缺乏通过G3BP1依赖性信号通路加重MIRI。因此，SHEP1-G3BP1相互作用对于SHEP1调节巨噬细胞的浸润和促炎反应是不可或缺的，这为MIRI提供了一个潜在的、具有临床意义的治疗靶点。
