The Ubiquitin Ligase MuRF1 Protects Against Cardiac Ischemia/Reperfusion Injury by Its Proteasome-Dependent Degradation of Phospho-c-Jun
The Ubiquitin Ligase MuRF1 Protects Against Cardiac Ischemia/Reperfusion Injury by Its Proteasome-Dependent Degradation of Phospho-c-Jun
复制标题
DOI：
10.1016/j.ajpath.2010.11.049
复制
发表时间：
2011-03-01
影响因子：
6
通讯作者：
Willis, Monte S.
中科院分区：
文献类型：
--
作者：
Li, Hui-Hua;Du, Jie;Willis, Monte S.
尽管急性冠脉综合征的干预措施有所改进，但恢复缺血心肌血流的初级再灌注治疗会激活导致心肌细胞死亡的信号级联反应。这些信号级联，包括丝裂原活化蛋白激酶信号通路，激活了心肌细胞对缺血和再灌流的反应死亡。肌环指蛋白-1(MuRF1)是一种心脏特异蛋白，通过其泛素连接酶活性调节心肌细胞质量，作用于降解肌节蛋白和抑制参与心肌肥大信号的转录因子。为探讨MuRF1‘S在心肌缺血/再灌注损伤中的作用，以培养的和完整的心肌细胞为模型，研究了MuRF1的存在和缺失对心肌细胞I/R损伤的影响。我们发现，MuRF1具有心脏保护作用，部分原因是它能够通过抑制Jun N末端激酶(INK)信号来防止细胞死亡。MuRF1专门针对JNK的近端下游靶点激活的磷酸化c-jun，使其被蛋白酶体降解，有效地抑制下游信号转导和诱导细胞死亡。MURF1‘S通过其泛素蛋白酶体依赖的降解活化的c-jun抑制JNK信号转导，是首次描述的心脏泛素连接酶抑制丝裂原活化蛋白激酶信号转导。MURF1‘S对心肌I/R损伤的保护作用可被体内JNK抑制减弱，提示MURF1’S对c-Jun的调节在完整心脏中具有显著作用。(Am J Pathol 2011,178：1043-1054.Doi：10.1016/j.ajpath.2010.11.049)
Despite improvements in interventions of acute coronary syndromes, primary reperfusion therapies restoring blood flow to ischemic myocardium leads to the activation of signaling cascades that induce cardiomyocyte cell death. These signaling cascades, including the mitogen-activated protein kinase signaling pathways, activate cardiomyocyte death in response to both ischemia and reperfusion. We have previously identified muscle ring finger-1 (MuRF1) as a cardiac-specific protein that regulates cardiomyocyte mass through its ubiquitin ligase activity, acting to degrade sarcomeric proteins and inhibit transcription factors involved in cardiac hypertrophy signaling. To determine MuRF1's role in cardiac ischemia/reperfusion (I/R) injury, cardiomyocytes in culture and intact hearts were challenged with I/R injury in the presence and absence of MuRF1. We found that MuRF1 is cardioprotective, in part, by its ability to prevent cell death by inhibiting Jun N-terminal kinase (INK) signaling. MuRF1 specifically targets JNK's proximal downstream target, activated phospho-c-Jun, for degradation by the proteasome, effectively inhibiting downstream signaling and the induction of cell death. MuRF1's inhibitory affects on JNK signaling through its ubiquitin proteasome-dependent degradation of activated c-Jun is the first description of a cardiac ubiquitin ligase inhibiting mitogen-activated protein kinase signaling. MuRF1's cardioprotection in I/R injury is attenuated in the presence of pharmacologic JNK inhibition in vivo, suggesting a prominent role of MuRF1's regulation of c-Jun in the intact heart. (Am J Pathol 2011, 178:1043-1054. DOI: 10.1016/j.ajpath.2010.11.049)