TY - JOUR
T1 - Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype
AU - Zhang, Min
AU - Wang, Caiping
AU - Wang, Rongning
AU - Xu, Jiean
AU - Wang, Zhefeng
AU - Yan, Jianlong
AU - Cai, Yongfeng
AU - Li, Liangping
AU - Huo, Yuqing
AU - Dong, Shaohong
N1 - Funding Information:
This work was supported by the Shenzhen Science and Technology Innovation Program ( JCYJ20210324112809025 ), China Postdoctoral Science Foundation ( 2019M650233 ), Guangdong Provincial Natural Science Foundation ( 2020A1515011311 ), and National Natural Science Foundation of China ( 82003020 ).
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.
AB - Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.
KW - Adenosine kinase
KW - Cardiac repair
KW - Histone methylation
KW - Macrophage polarization
KW - Myocardial infarction
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U2 - 10.1016/j.yjmcc.2022.11.007
DO - 10.1016/j.yjmcc.2022.11.007
M3 - Article
C2 - 36473288
SN - 0022-2828
VL - 174
SP - 88
EP - 100
JO - Journal of molecular and cellular cardiology
JF - Journal of molecular and cellular cardiology
ER -