Oxidative cross-linking of proteins to DNA following ischemia-reperfusion injury

Arnold Groehler, Stefan Kren, Qinglu Li, Maggie Robledo-Villafane, Joshua Schmidt, Mary Garry, Natalia Tretyakova

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Myocardial infarction (MI) is a life-threatening condition that can occur when blood flow to the heart is interrupted due to a blockage in one or more of the coronary vessels. Current treatments of MI rapidly restore blood flow to the affected myocardium using thrombolytic agents or angioplasty. Adverse effects including inflammation, tissue necrosis, and ventricular dysfunction are, however, not uncommon following reperfusion therapy. These conditions are thought to be caused by a sudden influx of reactive oxygen species (ROS) to the affected myocardium. We employed the model of left anterior descending artery ligation/reperfusion surgery in a rat model to show that ischemia/reperfusion injury is associated with the formation of toxic DNA-protein cross-links (DPCs) in cardiomyocytes. Mass spectrometry based experiments have revealed that these conjugates were formed by a free radical mechanism and involved thymidine residues of DNA and tyrosine side chains of proteins (dT-Tyr). Quantitative proteomics experiments have identified nearly 90 proteins participating in hydroxyl radical-induced DPC formation, including ROS scavengers, contractile proteins, and regulators of apoptosis. Global proteome changes were less pronounced and included increased expression of mitochondrial proteins required for aerobic respiration and biomarkers of sarcomere breakdown following ischemia/reperfusion injury. Overall, our results are consistent with a model where sudden return of oxygen to ischemic tissues induces oxidative stress, inflammation, and the formation of DNA-protein cross-links that may contribute to reperfusion injury by desregulating gene expression and inducing cardiomyocyte death.

Original languageEnglish (US)
Pages (from-to)89-101
Number of pages13
JournalFree Radical Biology and Medicine
Volume120
DOIs
StatePublished - May 20 2018

Bibliographical note

Funding Information:
This work was supported by the U.S. National Institute of Environmental Health Sciences [grant number R01 ES-023350 ].

Keywords

  • Cardiomyocytes
  • DNA-protein cross-linking
  • Ischemia-reperfusion injury
  • Mass spectrometry based proteomics
  • Reactive oxygen species

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