title: The ubiquitin ligase MuRF1 protects against cardiac ischemia/reperfusion injury by its proteasome-dependent degradation of phospho-c-Jun.
abstract: 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 (JNK) 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.
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China. hhli1935@yahoo.cn
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Yong-Na
authors.initials: YN
authors.lastname: Fan
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Zhang
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.forename: Luge
authors.initials: L
authors.lastname: Li
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockyer
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Kang
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*; D013379:Substrate Specificity / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; C413644:Rnf30 protein, mouse; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex