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

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.

Effects of intermittent hypoxia on the cell survival and inflammatory responses in the intertidal marine bivalves Mytilus edulis and Crassostrea gigas

“…Furthermore, reoxygenation can cause oxidative damage via a surge of reactive oxygen species (ROS) from the mitochondrial electron transport system (ETS) (Andrienko et al, 2017;Jastroch et al, 2010). Oxidative stress is considered a hallmark of the hypoxiareoxygenation (H-R) injury in hypoxia-sensitive organisms such as terrestrial mammals and, if left unchecked, leads to the accumulation of cellular damage and eventually cell death (Cadenas, 2018;Groehler et al, 2018;Ham and Raju, 2016;Hernansanz-Agustín et al, 2014). Studies in hypoxia-tolerant animals, such as freshwater turtles, crucian carp, and intertidal mollusks and fish, uncovered several putative mitochondrial mechanisms that can mitigate oxidative stress during H-R.…”

N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis

“…Inflammation is another well-known process after myocardial I/R injury, leading to death of cardiomyocytes. In our study, we assessed oxidative stress and inflammatory factors after ROSC, and established that oxidative stress and inflammation were involved in myocardial dysfunction, as other studies have similarly shown [11][12][13].…”

“…ROS, which is released during the I/R process, promotes tissue inflammation, and activates immune responses through NLRP3 inflammasome, inducing the secretion of pro-inflammatory cytokine Interleukin 1β(IL-1β) and cell pyroptosis [ 10 ]. Recent studies showed that NAC suppressed cardiomyocytes pyroptosis by inhibiting ROS in a myocardial infarction model [ 11 – 13 ].…”

Metabolomics investigation of molecular responses of whiteleg shrimp (Penaeus vannamei) to hypoxia

“…Acute hypoxia was found to induce oxidative stress due to the excessive reactive oxygen species (ROS) production in P. vannamei [79,80]. Oxidative damage due to the excessive ROS production is considered a major contributor to oxidative injury during hypoxia-reoxygenation stress [81][82][83]. Glutathione is an antioxidant that effectively scavenges free radicals such as ROS and reactive nitrogen species (RNS) (e.g., hydroxyl radical, hydrogen peroxide, lipid peroxyl radical and superoxide anion) directly and indirectly through the glutathione cycle [84].…”