2. Academic Validation
  3. Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype

Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype

  • J Mol Cell Cardiol. 2022 Dec 3;174:88-100. doi: 10.1016/j.yjmcc.2022.11.007.
Min Zhang 1,  Caiping Wang 2,  Rongning Wang 2,  Jiean Xu 3,  Zhefeng Wang 1,  Jianlong Yan 2,  Yongfeng Cai 3,  Liangping Li 4,  Yuqing Huo 5,  Shaohong Dong 6
Affiliations

Affiliations

  • 1 Department of Cardiology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China; The First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
  • 2 Department of Cardiology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 4 The First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Institute of Clinical Oncology, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
  • 5 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, GA 30912, United States.
  • 6 Department of Cardiology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China. Electronic address: [email protected].
PMID: 36473288 DOI: 10.1016/j.yjmcc.2022.11.007
Abstract

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.

Keywords

Adenosine kinase; Cardiac repair; Histone methylation; Macrophage polarization; Myocardial infarction.

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