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A novel function of nuclear nonmuscle myosin regulatory light chain in promotion of xanthine oxidase transcription after myocardial ischemia/reperfusion.

Abstract
Nuclear myosin regulates gene transcription and this novel function might be modulated through phosphorylation of the myosin regulatory light chain (p-MLC20). Nonmuscle MLC20 (nmMLC20) is also present in the nuclei of cardiomyocytes and a potential nmMLC20 binding sequence has been identified in the promoter of the xanthine oxidase (XO) gene. Thus, we investigated its function in the regulation of XO transcription after myocardial ischemia/reperfusion (IR). In a rat model of myocardial IR and a cardiomyocyte model of hypoxia/reoxygenation (HR) injury, the cardiac or cell injury, myosin light chain kinase (MLCK) content, XO expression and activity, XO-derived products, and level of nuclear p-nmMLC20 were detected. Coimmunoprecipitation (co-IP), chromatin immunoprecipitation, DNA pull-down, and luciferase reporter gene assays were used to decipher the molecular mechanisms through which nmMLC20 promotes XO expression. IR or HR treatment dramatically elevated nuclear p-nmMLC20 level, accompanied by increased XO expression, activity, and products (H2O2 and uric acid), as well as the IR or HR injury; these effects were ameliorated by inhibition of MLCK or knockdown of nmMLC20. Our findings from these experiments demonstrated that nuclear p-nmMLC20 binds to the consensus sequence GTCGCC in the XO gene promoter, interacts with RNA polymerase II and transcription factor IIB to form a transcription preinitiation complex, and hence activates XO gene transcription. These results suggest that nuclear p-nmMLC20 plays an important role in IR/HR injury by transcriptionally upregulating XO gene expression to increase oxidative stress in myocardium. Our findings demonstrate nuclear nmMLC20 as a potential new therapeutic target to combat cardiac IR injury.
AuthorsYi-Shuai Zhang, Bin Liu, Xiu-Ju Luo, Jie-Jie Zhang, Nian-Sheng Li, Qi-Lin Ma, Jun-Lin Jiang, Yuan-Jian Li, Qingjie Li, Jun Peng
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 83 Pg. 115-28 (Jun 2015) ISSN: 1873-4596 [Electronic] United States
PMID25701432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Myosin Light Chains
  • RNA, Messenger
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Xanthine Oxidase
Topics
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Nucleus (genetics, metabolism)
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Enzymologic
  • Hydrogen Peroxide (metabolism)
  • Immunoprecipitation
  • Male
  • Myocardial Ischemia (genetics, metabolism, pathology)
  • Myocardial Reperfusion Injury (genetics, metabolism, pathology)
  • Myosin Light Chains (genetics, metabolism)
  • Oxidative Stress
  • RNA, Messenger (genetics)
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species (metabolism)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xanthine Oxidase (genetics, metabolism)

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