title: Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury.
abstract: This study aimed to investigate whether interferon regulatory factor 9 (IRF9) is involved in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury and to explore the underlying molecular mechanisms of this process. Cell death plays a major role in myocardial I/R injury. We recently determined the importance of IRF9 in coordinating molecular events in response to hypertrophic stress in cardiomyocytes. However, the roles of IRF9 in lethal myocardial injury remain to be elucidated. The involvement of IRF9 was assessed via functional assays in a mouse myocardial I/R injury model by genetic knockout and cardiomyocyte-specific transgenic overexpression of IRF9, and its effects on cardiomyocyte apoptosis and inflammation were further studied in vivo and in vitro. IRF9 was upregulated in human ischemic heart tissue and mouse hearts after I/R injury. Ablation of IRF9 protected the heart against I/R-induced cardiomyocyte death, development of inflammation, and loss of heart function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF9 aggravated myocardial reperfusion injury and inflammation. IRF9 negatively regulated the Sirt1-p53 axis under I/R conditions in vivo and in vitro. Downregulation of Sirt1 expression and its downstream apoptosis-related signaling cascade, which results from I/R, was ameliorated by loss of IRF9 and exacerbated by overexpression of IRF9. Cardiomyocyte-specific deletion of Sirt1 abolished the protective effect of IRF9 knockout against I/R injury, which further indicated that IRF9 mediated myocardial reperfusion injury by modulating the Sirt1-p53 axis. Thus, IRF9 may be a novel therapeutic target for the prevention of I/R injury resulting from revascularization therapy after acute myocardial infarction (MI).
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Liu
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Nian
authors.initials: N
authors.lastname: Wan
authors.forename: Hao
authors.initials: H
authors.lastname: Xia
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Zhu
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; C494227:IRF9 protein, human; C000595409:IRF9 protein, rat; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C494228:Isgf3g protein, mouse