| First Author | Gu SX | Year | 2016 |
| Journal | JCI Insight | Volume | 1 |
| Issue | 7 | PubMed ID | 27294204 |
| Mgi Jnum | J:293591 | Mgi Id | MGI:6442502 |
| Doi | 10.1172/jci.insight.86460 | Citation | Gu SX, et al. (2016) Protein methionine oxidation augments reperfusion injury in acute ischemic stroke. JCI Insight 1(7):e86460 |
| abstractText | 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-kappaB 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-kappaB 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-kappaB 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-kappaB or CaMKII. MsrA-deficient mice also exhibited enhanced leukocyte rolling and upregulation of E-selectin, an endothelial NF-kappaB-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-kappaB activation, leading to neutrophil recruitment and neurovascular inflammation in acute ischemic stroke. |
