Abstract | OBJECTIVE: To investigate whether lipoxin A4 ( LXA4) increases expression of heme oxygenase-1(HO-1) in cardiomyocytes, whether LXA4-induced HO-1 protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and what are the mechanisms involved in the LXA4-induced HO-1 induction. METHODS: Rat cardiomyocytes were exposed to H/R injury with or without preincubation with LXA4 or HO-1 inhibitor ZnPP-IX or various signal molecule inhibitors. Expressions of HO-1 protein and mRNA were analyzed by using Western blot and RT-PCR respectively. Activity of nuclear factor E2-related factor 2 (Nrf2) binding to the HO-1 E1 enhancer was assessed by chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) were measured by using electrophoretic mobility shift assay. RESULTS: Pretreatment of the cells undergoing H/R lesion with LXA4 significantly reduced the lactate dehydrogenase and creatine kinase productions, increased the cell viability, and increased the expressions of HO-1 protein and mRNA and HO-1 promoter activity. HO-1 inhibition abolished the protective role of LXA4 on the cells undergoing H/R lesion. LXA4 increased p38 mitogen-activated protein kinase ( p38 MAPK) activation, nuclear translocation of Nrf2, Nrf2 binding to the HO-1 ARE and E1 enhancer in cardiomyocytes with or without H/R exposure. CONCLUSION: The protection role of LXA4 against H/R injury of cardiomyocytes is related to upregulation of HO-1, via activation of p38 MAPK pathway and nuclear translocation of Nrf2 and Nrf2 binding to the HO-1 ARE and E1 enhancer, but not via activation of phosphatidyinositol-3-kinase or extracellular signal-regulated kinase pathway.
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Authors | Xiao-Qing Chen, Sheng-Hua Wu, Yu Zhou, Yan-Rong Tang |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 6
Pg. e67120
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23826208
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cardiotonic Agents
- Lipoxins
- NF-E2-Related Factor 2
- lipoxin A4
- L-Lactate Dehydrogenase
- Heme Oxygenase-1
- Phosphatidylinositol 3-Kinases
- Proto-Oncogene Proteins c-akt
- p38 Mitogen-Activated Protein Kinases
- Creatine Kinase
- Oxygen
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Topics |
- Animals
- Antioxidant Response Elements
(genetics)
- Cardiotonic Agents
(pharmacology)
- Cell Shape
(drug effects)
- Cell Survival
(drug effects)
- Creatine Kinase
(metabolism)
- Enzyme Induction
(drug effects)
- Heme Oxygenase-1
(biosynthesis, genetics)
- Hypoxia
(enzymology, genetics, pathology)
- L-Lactate Dehydrogenase
(metabolism)
- Lipoxins
(pharmacology)
- Male
- Myocytes, Cardiac
(drug effects, enzymology, pathology)
- NF-E2-Related Factor 2
(metabolism)
- Oxygen
(metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Protein Transport
(drug effects)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Rats
- Rats, Wistar
- Transcription, Genetic
(drug effects)
- Up-Regulation
(drug effects)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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