Astrocyte-derived glutathione attenuates hemin-induced apoptosis in cerebral microvascular cells

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Intracerebral hemorrhage (ICH) induces neurovascular injury via poorly defined mechanisms. The aim of this study was to determine whether gliovascular communication may restrict hemorrhagic vascular injury. Hemin, a hemoglobin by-product, concentrationand time-dependently increased apoptotic cell death in mouse bEnd.3 cells and in primary human brain microvascular endothelial cells, at least in part, via a caspase-3 dependent pathway. Cell death was preceded by a NFκB-mediated increase in inflammatory gene expression, including upregulation of inducible nitric oxide synthase (iNOS) expression and activity. Functionally, inhibition of iNOS or the addition of a peroxynitrite decomposition catalyst reduced cell death. Interestingly, co-treatment with astrocyte-conditioned media (ACM) reversed hemin-induced NFjB activation, nitrotyrosine formation, and apoptotic cell death, at least in part, via the release of the endogenous antioxidant, reduced glutathione (GSH). Prior treatment of astrocytes with the GSH-depleting agent, DLbuthionine (S,R)-sulfoximine or direct addition of diethyl maleate, a thiol-depleting agent, to ACM reversed the observed protection. In contrast, neither exogenous GSH nor the GSH precursor, N-acetylcysteine, was protective in bEnd.3 cells. Together, these data support an important role for astrocyte-derived GSH in the maintenance of oxidative balance in the vasculature and suggest therapeutic targeting of the GSH system may reduce neurological injury following ICH.

Original languageEnglish (US)
Pages (from-to)1858-1870
Number of pages13
JournalGlia
Volume58
Issue number15
DOIs
StatePublished - Nov 15 2010

Fingerprint

Hemin
Astrocytes
Glutathione
Cell Death
Apoptosis
diethyl maleate
Cerebral Hemorrhage
Nitric Oxide Synthase Type II
Conditioned Culture Medium
Peroxynitrous Acid
Vascular System Injuries
Wounds and Injuries
Acetylcysteine
Sulfhydryl Compounds
Caspase 3
Hemoglobins
Up-Regulation
Endothelial Cells
Antioxidants
Communication

Keywords

  • Anti-oxidant
  • Blood-brain barrier
  • GSH
  • Glia
  • Neurovascular

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Astrocyte-derived glutathione attenuates hemin-induced apoptosis in cerebral microvascular cells. / Sukumari Ramesh, Sangeetha; Laird, Melissa D.; Singh, Nagendra; Vender, John R; Alleyne, Cargill Herley; Dhandapani, Krishnan Michael.

In: Glia, Vol. 58, No. 15, 15.11.2010, p. 1858-1870.

Research output: Contribution to journalArticle

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