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: Hui-Hua Li, Jie Du, Yong-Na Fan, Mei-Li Zhang, De-Pei Liu, Luge Li, Pamela Lockyer, Eunice Y Kang, Cam Patterson, Monte S Willis
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 3 Pg. 1043-58 (Mar 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21356357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cardiotonic Agents
• Muscle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-jun
• Rnf30 protein, mouse
• Tripartite Motif Proteins
• Trim63 protein, mouse
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex

Topics

• Animals
• Cardiotonic Agents (metabolism)
• Cell Death (drug effects)
• Cell Line
• Conserved Sequence (genetics)
• Humans
• In Vitro Techniques
• Mice
• Mice, Transgenic
• Muscle Proteins (metabolism)
• Myocardial Ischemia (enzymology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Reperfusion Injury (enzymology, prevention & control)
• Substrate Specificity (drug effects)
• Transcriptional Activation (drug effects, genetics)
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination (drug effects)