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5-Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect
Hye-Yun Jeong1,2, Wan Seok Kang1,2, Moon Hwa Hong1
1Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.
Abstract:
Macrophages are actively involved in inflammatory responses during the progression of cardiac injury, including myocardial infarction (MI). A previous study showed that 5-azacytidine (5AZ), a DNA methylation inhibitor, can ameliorate cardiac injury by shifting macrophages toward an anti-inflammatory phenotype via iNOS inhibition. Here, we show that the beneficial effect of 5AZ is associated with sumoylation of interferon regulatory factor-1 (IRF1) in macrophages. IRF1 is a critical transcription factor for iNOS induction and is antagonized by IRF2. In the stimulated macrophages, IRF1 accumulated in the nucleus without degradation by 5AZ treatment. In animal study, 5AZ administration resulted in significant improvements in cardiac function and fibrosis. IRF1-expressing macrophages were more abundant in the 5AZ-treated MI group than in the PBS-treated MI group. Because sumoylated IRF1 is known to mimic IRF2, we examined the IRF1 sumoylation. Sumoylated IRF1 was resistant to degradation and significantly increased in the 5AZ-treated MI group. Collectively, 5AZ had a protective effect after MI by potentiation of IRF1 sumoylation and is suggested as a novel therapeutic intervention for cardiac repair.
Insights
5-azacytidine (5AZ) protects against cardiac injury by enhancing the anti-inflammatory properties of macrophages. This involves increasing sumoylated interferon regulatory factor-1 (IRF1), a key factor in reducing inflammation after myocardial infarction (MI).
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Macrophages play a crucial role in cardiac injury, such as myocardial infarction (MI).
- DNA methylation inhibitors, like 5-azacytidine (5AZ), can modulate macrophage inflammatory responses.
- Interferon regulatory factor-1 (IRF1) is a key transcription factor in iNOS induction and inflammatory pathways.
Purpose of the Study:
- To investigate the mechanism by which 5AZ ameliorates cardiac injury.
- To explore the role of IRF1 sumoylation in 5AZ-mediated cardioprotection.
- To evaluate 5AZ as a potential therapeutic for myocardial infarction.
Main Methods:
- In vitro studies on stimulated macrophages treated with 5AZ.
- In vivo animal study using a myocardial infarction model.
- Analysis of IRF1 expression, nuclear localization, and sumoylation status.
Main Results:
- 5AZ treatment led to increased sumoylation of IRF1 in macrophages.
- Sumoylated IRF1 accumulated in the nucleus and resisted degradation.
- 5AZ administration improved cardiac function and reduced fibrosis in a mouse MI model.
- Increased abundance of IRF1-expressing macrophages was observed in 5AZ-treated MI hearts.
Conclusions:
- 5AZ confers a protective effect in myocardial infarction by enhancing IRF1 sumoylation.
- This mechanism involves shifting macrophages towards an anti-inflammatory phenotype.
- 5AZ represents a promising novel therapeutic strategy for cardiac repair post-MI.
