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. 2024 Jan 5:126:111216.
doi: 10.1016/j.intimp.2023.111216. Epub 2023 Nov 15.

MFG-E8 facilitates heart repair through M1/M2 polarization after myocardial infarction by inhibiting CaMKII

Peiwu Ding  1 , Jie Liu  1 , Yidi Meng  2 , Hongfei Wang  3 , Yun Huang  4 , Guanhua Su  5 , Chaorui Xia  5 , Xinling Du  3 , Nianguo Dong  3 , Tianpen Cui  6 , Jiaming Zhang  5 , Jingdong Li  7
Affiliations
Free article

MFG-E8 facilitates heart repair through M1/M2 polarization after myocardial infarction by inhibiting CaMKII

Peiwu Ding et al. Int Immunopharmacol. .
Free article

Abstract

Background: M1/M2 macrophage polarization affects patient outcomes after myocardial infarction (MI). The relationship between milk fat globule-epidermal growth factor 8 (MFG-E8) and Ca2+/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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Ca(2+)/calmodulin-dependent protein kinase II; M1 macrophages; M2 macrophages; Macrophage polarization; Milk fat globule-epidermal growth factor 8; Myocardial infarction.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. CRediT authorship contribution statement Peiwu Ding: Conceptualization, Investigation, Methodology, Formal analysis, Writing - review & editing. Jie Liu: Investigation, Methodology, Writing-original draft. Yidi Meng : Investigation, Funding acquisition, Methodology. Hongfei Wang : Supervision. Chaorui Xia: Methodology. Yun Huang: Methodology. Guanhua Su: Supervision. Jiaming Zhang: Investigation, Methodology. Tianpen Cui: Resources, Methodology. Xinling Du: Resources. Nianguo Dong: Resources. Jingdong Li: Conceptualization, Investigation, Methodology, Funding acquisition, Formal analysis, Writing - review & editing.