Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex.

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.

• 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)

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

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)