Rescue of neurons from ischemic injury by peroxisome proliferator-activated receptor-gamma requires a novel essential cofactor LMO4.
Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPARgamma signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPARgamma agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIIalphaCre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPARgamma-protective effect. PPARgamma signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [manganese(III)tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPARgamma signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPARgamma and PGC1alpha (PPARgamma coactivator 1alpha) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed that LMO4 interacts in a ligand-dependent manner with PPARgamma. LMO4 augments PPARgamma-dependent gene activation, in part, by promoting RXRalpha (retinoid X receptor-alpha) binding to PPARgamma and by increasing PPARgamma binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPARgamma signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.
Schock
Sarah C
SC
Ottawa Health Research Institute, Neuroscience, Ottawa, Ontario, Canada K1H 8M5.
Xu
Jin
J
Duquette
Philippe M
PM
Qin
Zhaohong
Z
Lewandowski
Adam J
AJ
Rai
Punarpreet S
PS
Thompson
Charlie S
CS
Seifert
Erin L
EL
Harper
Mary-Ellen
ME
Chen
Hsiao-Huei
HH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D018398:Homeodomain Proteins / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007608:Kainic Acid / Q000494:pharmacology; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000008:administration & dosage; D047495:PPAR gamma / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D000099156:Superoxide Dismutase 2
D048868:Adaptor Proteins, Signal Transducing; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007608:Kainic Acid; D060588:LIM Domain Proteins; D016202:N-Methylaspartate; D010100:Oxygen; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077154:Rosiglitazone; D013482:Superoxide Dismutase; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C491976:Lmo4 protein, mouse; C485290:Ppargc1a protein, mouse