title: Myristoylated methionine sulfoxide reductase A protects the heart from ischemia-reperfusion injury.
abstract: Methionine sulfoxide reductase A (MsrA) catalytically scavenges reactive oxygen species and also repairs oxidized methionines in proteins. Increasing MsrA protects cells and organs from a variety of oxidative stresses while decreasing MsrA enhances damage, but the mechanisms of action have not been elucidated. A single gene encodes MsrA of which ∼25% is targeted to the mitochondria, a major site of reactive oxygen species production. The other ∼75% is targeted to the cytosol and is posttranslationally modified by myristoylation. To determine the relative importance of MsrA in each compartment in protecting against ischemia-reperfusion damage, we created a series of transgenic mice overexpressing MsrA targeted to the mitochondria or the cytosol. We used a Langendorff model of ischemia-reperfusion and assayed both the rate pressure product and infarct size following ischemia and reperfusion as measures of injury. While the mitochondrially targeted MsrA was expected to be protective, it was not. Notably, the cytosolic form was protective but only if myristoylated. The nonmyristoylated, cytosolic form offered no protection against injury. We conclude that cytosolic MsrA protects the heart from ischemia-reperfusion damage. The requirement for myristoylation suggests that MsrA must interact with a hydrophobic domain to provide protection.
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-8012, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhao
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Anne M
authors.initials: AM
authors.lastname: Deschamps
authors.forename: Geumsoo
authors.initials: G
authors.lastname: Kim
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D007150:Immunohistochemistry; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D051150:Methionine Sulfoxide Reductases