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Exp. Mol. Med., Sep 12 2024, | https://doi.org/10.1038/s12276-024-01304-0 IKKε-deficient macrophages impede cardiac repair after myocardial infarction by enhancing the macrophage-myofibroblast transition

Hyang Hee Cho^1,9, Siyeon Rhee^2,9, Dong Im Cho¹, Ju Hee Jun¹, HyoJung Heo³, Su Han Cho⁴, Dohyup Kim⁵, Mingqiang Wang², Bo Gyeong Kang¹, Soo Ji Yoo¹, Meeyoung Cho¹, Soo yeon Lim¹, Jae Yeong Cho⁶, In Seok Jeong⁷, Yong Sook Kim^1,8 and Youngkeun Ahn^1,6

¹Cell Regeneration Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.

²Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.

³Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.

⁴Department of Biology, Kyung Hee University, Seoul, Republic of Korea.

⁵Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.

⁶Department of Cardiology, Chonnam National University Hospital and Medical School, Gwangju, Republic of Korea.

⁷Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital and Medical School, Gwangju, Republic of Korea.

⁸Biomedical Research Institute, Chonnam National University Hospital, Gwangju, Republic of Korea.

⁹These authors contributed equally: Hyang Hee Cho, Siyeon Rhee

Corresponding authors

Correspondence to Yong Sook Kim or Youngkeun Ahn.

Abstract

The regulatory role of the inhibitor of NF-kB kinase ε (IKKε) in postmyocardial infarction (MI) inflammation remains uncertain. Using an MI mouse model, we examined the cardiac outcomes of IKKε knockout (KO) mice and wild-type mice. We employed single-cell RNA sequencing (scRNA-seq) and phosphorylated protein array techniques to profile cardiac macrophages. IKKε KO mice exhibited compromised survival, heightened inflammation, pronounced cardiac fibrosis, and a reduced ejection fraction. A distinct cardiac macrophage subset in IKKε KO mice exhibited increased fibrotic marker expression and decreased phosphorylated p38 (p-p38) levels, indicating an enhanced macrophage-myofibroblast transition (MMT) post-MI. While cardiac inflammation is crucial for initiating compensatory pathways, the timely resolution of inflammation was impaired in the IKKε KO group, while the MMT in macrophages accelerated post-MI, leading to cardiac failure. Additionally, our study highlighted the potential of 5-azacytidine (5-Aza), known for its anti-inflammatory and cardioprotective effects, in restoring p-p38 levels in stimulated macrophages. The administration of 5-Aza significantly reduced the MMT in cardiac macrophages from the IKKε KO group. These findings underscore the regulation of the inflammatory response and macrophage transition by the IKKε-p38 axis, indicating that the MMT is a promising therapeutic target for ischemic heart disease.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-13)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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