5-Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect.
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.
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.|Department of Molecular Medicine, Graduate School, Chonnam National University, Gwangju, Republic of Korea.
Hye-Yun
HY
Jeong
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.|Department of Molecular Medicine, Graduate School, Chonnam National University, Gwangju, Republic of Korea.
Wan Seok
WS
Kang
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.
Moon Hwa
MH
Hong
Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.
Hae Chang
HC
Jeong
Department of Laboratory Medicine, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.
Myun-Geun
MG
Shin
Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.
Myung Ho
MH
Jeong
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.|Biomedical Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.
Yong Sook
YS
Kim
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Republic of Korea.|Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.
Youngkeun
Y
Ahn
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis*; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D041681:NIH 3T3 Cells; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D058207:Sumoylation / Q000187:drug effects
D002316:Cardiotonic Agents; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001374:Azacitidine