Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int Immunopharmacol. 2024 Jan 5;126:111216. doi: 10.1016/j.intimp.2023.111216. Epub 2023 Nov 15.
M1/M2 macrophage polarization affects patient outcomes after myocardial infarction (MI). The relationship between milk fat globule-epidermal growth factor 8 (MFG-E8) and Ca/calmodulin-dependent protein kinase II (CaMKII) on macrophage polarization after MI is unknown. To investigate the functional role of MFG-E8 in modulating cardiac M1/M2 macrophage polarization after MI, especially its influence on CaMKII signaling.
Human ventricular tissue and blood were obtained from patients with MI and controls. MFG-E8-KO mice were constructed (C57BL/6). The mice were randomized to WT-sham, sham-MFG-E8-KO, WT-PBS, rmMFG-E8 (WT injected with rmMFG-E8 10 min after MI), and MFG-E8-KO. The mouse macrophage cell line RAW264.7 was obtained. CaMKII, p-CaMKII, Akt, and NF-κB p65 were determined by qRT-PCR, western blot, and immunofluorescence.
The MFG-E8 levels were significantly enhanced after MI in the hearts and plasma of patients with MI compared with controls. The MFG-E8 levels were significantly increased in the hearts and plasma of mice after MI. MFG-E8 was derived from cardiac fibroblasts. The administration of rmMFG-E8 improved ventricular remodeling and cardiac function after MI. rmMFG-E8 did not suppress infiltrating monocyte/macrophages into the peri-infarct area. rmMFG-E8 suppressed the polarization of macrophages to the M1 phenotype and promoted the polarization of macrophages to the M2 phenotype. rmMFG-E8 suppressed CaMKII-dependent signaling in macrophages.
MFG-E8 and CaMKII appear to collaboratively regulate myocardial remodeling and M1/M2 macrophage polarization after MI. These observations suggest new roles for MFG-E8 in inhibiting M1 but promoting M2 macrophage polarization.
M1/M2 巨噬细胞极化影响心肌梗死后患者的预后。牛奶脂肪球表皮生长因子 8（MFG-E8）与钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）在心肌梗死后巨噬细胞极化中的关系尚不清楚。为了研究 MFG-E8 在调节心肌梗死后心脏 M1/M2 巨噬细胞极化中的功能作用，特别是其对 CaMKII 信号的影响。
从心肌梗死患者和对照者中获得人心室组织和血液。构建 MFG-E8-KO 小鼠（C57BL/6）。将小鼠随机分为 WT-假手术、假手术-MFG-E8-KO、WT-PBS、rmMFG-E8（WT 在心肌梗死后 10 分钟注射 rmMFG-E8）和 MFG-E8-KO。获得小鼠巨噬细胞系 RAW264.7。通过 qRT-PCR、western blot 和免疫荧光测定 CaMKII、p-CaMKII、Akt 和 NF-κB p65。
与对照组相比，心肌梗死后患者心脏和血浆中的 MFG-E8 水平显著升高。心肌梗死后小鼠心脏和血浆中的 MFG-E8 水平显著升高。MFG-E8 来源于心肌成纤维细胞。rmMFG-E8 改善了心肌梗死后的心室重构和心功能。rmMFG-E8 并没有抑制单核细胞/巨噬细胞浸润到梗死周围区。rmMFG-E8 抑制了巨噬细胞向 M1 表型的极化，并促进了巨噬细胞向 M2 表型的极化。rmMFG-E8 抑制了巨噬细胞中的 CaMKII 依赖性信号。
MFG-E8 和 CaMKII 似乎协同调节心肌梗死后的心肌重构和 M1/M2 巨噬细胞极化。这些观察结果表明 MFG-E8 在抑制 M1 但促进 M2 巨噬细胞极化方面具有新的作用。
