title: Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.
abstract: Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nagata
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kyogoku
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Toyoharu
authors.initials: T
authors.lastname: Oba
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Jinya
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Nohara
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minami
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mawatari
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sugi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Koutatsu
authors.initials: K
authors.lastname: Shimozono
authors.affiliation: Lausanne Genomic Technologies Facility (LGTF), University of Lausanne, Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.affiliation: Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: Fukuoka Sanno Hospital and International University of Health and Welfare, Fukuoka, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D017353:Gene Deletion; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C579094:Mcl1 protein, mouse; D009124:Muscle Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3