Melatonin ameliorates ischemic-like injury-evoked nitrosative stress: Involvement of HtrA2/PED pathways in endothelial cells

Feng Han, Rong Rong Tao, Gen Sheng Zhang, Ying Mei Lu, Lu Lu Liu, Ying Xian Chen, Yi Jia Lou, Kohji Fukunaga, Ze Hui Hong

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Peroxynitrite contributes to diverse cellular stresses in the pathogenesis of ischemic complications. Here, we investigate the downstream effector signaling elements of nitrosative stress which regulate ischemia-like cell death in endothelial cells and protective effect of melatonin. When the mitochondrial membrane potential (ΔΨm) of oxygen-glucose deprivation (OGD)-treated cells was assessed using the fluorescent probe 5,5′,6,6′- tetrachloro-1,1′,3,3′-tetraethylbenzimidazol -carbocyanine iodide, we observed spontaneous changes in peroxynitrite formation. Concomitantly, western blot and confocal microscopy analyses indicated that prolonged OGD exposure initiates the release of mitochondrial HtrA2 and dramatically decreases phosphoprotein enriched in astrocytes (PED or PEA-15) protein levels. Consistently, cultured endothelial cells treated with peroxynitrite (1-50 μm) exhibited a concentration-dependent release of mitochondrial HtrA2 and concomitant PED degradation in vitro. Notably, HtrA2 activation coincided with increased nitrotyrosine immunoreactivity in microvessels of rats following microsphere embolism. Additionally, the protective effect of PED overexpression in OGD-induced apoptosis was abolished by transfection with the PED S104A/S116A mutant. Furthermore, the effect of melatonin, an potential antioxidant, on endothelial apoptotic cascade was examined in OGD-evoked nitrosative stress. Our data showed that the application of melatonin provided significant protection against OGD-induced peroxynitrite formation and mitochondrial HtrA2 release, accompanied with a decrease in degradation PED and x-linked inhibitor of apoptosis protein, which is associated with activation of the caspase cascade. Taken together, the protective effect of melatonin is likely mediated, in part, by inhibition of peroxynitrate-mediated nitrosative stress, which in turn relieves imbalance of mitochondrial HtrA2-PED signaling and endothelial cell death.

Original languageEnglish
Pages (from-to)281-291
Number of pages11
JournalJournal of Pineal Research
Volume50
Issue number3
DOIs
Publication statusPublished - 2011 Apr

Keywords

  • Endothelial cells
  • HtrA2
  • Melatonin
  • Mitochondria
  • Nitrosative stress
  • Oxygen-glucose deprivation

ASJC Scopus subject areas

  • Endocrinology

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