Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.
Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.
复制标题
DOI：
10.1371/journal.pone.0127942
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Imaizumi T
中科院分区：
文献类型：
--
作者：
Nagata T;Yasukawa H;Kyogoku S;Oba T;Takahashi J;Nohara S;Minami T;Mawatari K;Sugi Y;Shimozono K;Pradervand S;Hoshijima M;Aoki H;Fukumoto Y;Imaizumi T
心肌缺血再灌注损伤（IRI）对急性心肌梗死患者的心脏功能和预后有不利影响。尽管心肌信号换能器和转录激活因子（STAT） 3在IRI中具有强大的心脏保护作用，但其激活的抑制机制在很大程度上是未知的。本研究旨在探讨心肌细胞因子信号传导抑制因子(SOCS)-3在心肌IRI发生中的作用，SOCS -3是Janus激酶(JAK)-STAT信号通路的内在负反馈调节因子。结扎小鼠左冠状动脉前降支1 h，再灌注不同时间，诱导心肌IRI。再灌注1小时后观察jak - stat激活细胞因子的快速表达。我们在野生型和心脏特异性SOCS3敲除小鼠（SOCS3- cko）中精确评估了心肌保护信号分子的磷酸化和SOCS3在IRI期间的表达，然后诱导心肌IRI。STAT3、AKT和ERK1/2的激活在IRI期间迅速达到峰值并迅速下降。这种减少与野生型小鼠在IRI后24小时内诱导SOCS3表达相关。与野生型小鼠相比，SOCS3-CKO再灌注后24 h梗死面积明显减小。在SOCS3-CKO小鼠中，STAT3、AKT和ERK1/2磷酸化持续，心肌凋亡被阻止，抗凋亡Bcl-2家族成员髓样细胞白血病-1 （Mcl-1）表达增强。心脏特异性SOCS3缺失导致心脏保护信号分子持续激活，包括并阻止IRI期间心肌凋亡和损伤。我们的研究结果表明，SOCS3可能是加剧心肌IRI发展的关键因素。
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.
登录
查看更多内容
影响因子：
9.5
作者：
Boengler K;Hilfiker-Kleiner D;Heusch G;Schulz R
通讯作者：
Schulz R
影响因子：
20.1
作者：
Hamanaka, I;Saito, Y;Nakao, K
通讯作者：
Nakao, K
影响因子：
37.8
作者：
Negoro, S;Kunisada, K;Yamauchi-Takihara, K
通讯作者：
Yamauchi-Takihara, K
影响因子：
37.8
作者：
Lecour, S;Suleman, N;Opie, LH
通讯作者：
Opie, LH
影响因子：
5
作者：
Hattori, R;Maulik, N;Das, DK
通讯作者：
Das, DK