Journal article
Protein methionine oxidation augments reperfusion injury in acute ischemic stroke
JCI insight, Vol.1(7), e86460
2016
DOI: 10.1172/jci.insight.86460
PMCID: PMC4902298
PMID: 27294204
Abstract
Reperfusion injury can exacerbate tissue damage in ischemic stroke, but little is known about the mechanisms linking ROS to stroke severity. Here, we tested the hypothesis that protein methionine oxidation potentiates NF-κB activation and contributes to cerebral ischemia/reperfusion injury. We found that overexpression of methionine sulfoxide reductase A (MsrA), an antioxidant enzyme that reverses protein methionine oxidation, attenuated ROS-augmented NF-κB activation in endothelial cells, in part, by protecting against the oxidation of methionine residues in the regulatory domain of calcium/calmodulin-dependent protein kinase II (CaMKII). In a murine model, MsrA deficiency resulted in increased NF-κB activation and neutrophil infiltration, larger infarct volumes, and more severe neurological impairment after transient cerebral ischemia/reperfusion injury. This phenotype was prevented by inhibition of NF-κB or CaMKII. MsrA-deficient mice also exhibited enhanced leukocyte rolling and upregulation of E-selectin, an endothelial NF-κB-dependent adhesion molecule known to contribute to neurovascular inflammation in ischemic stroke. Finally, bone marrow transplantation experiments demonstrated that the neuroprotective effect was mediated by MsrA expressed in nonhematopoietic cells. These findings suggest that protein methionine oxidation in nonmyeloid cells is a key mechanism of postischemic oxidative injury mediated by NF-κB activation, leading to neutrophil recruitment and neurovascular inflammation in acute ischemic stroke.
Details
- Title: Subtitle
- Protein methionine oxidation augments reperfusion injury in acute ischemic stroke
- Creators
- Sean X Gu - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAIlya O Blokhin - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAKatina M Wilson - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USANirav Dhanesha - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAPrakash Doddapattar - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAIsabella M Grumbach - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAAnil K Chauhan - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USASteven R Lentz - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.1(7), e86460
- DOI
- 10.1172/jci.insight.86460
- PMID
- 27294204
- PMCID
- PMC4902298
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- R01 HL118742 / NHLBI NIH HHS I01 BX000163 / BLRD VA P01 HL062984 / NHLBI NIH HHS R01 HL118246 / NHLBI NIH HHS R01 HL108932 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984094527702771
Metrics
9 Record Views