Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines

Bryan A. Haines, Suresh L. Mehta, Serena M. Pratt, Craig H Warden, P. Andy Li

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Mitochondrial hyperpolarization inhibits the electron transport chain and increases incomplete reduction of oxygen, enabling production of reactive oxygen species (ROS). The consequence is mitochondrial damage that eventually causes cell death. Uncoupling proteins (UCPs) are inner mitochondrial membrane proteins that dissipate the mitochondrial proton gradient by transporting H across the inner membrane, thereby stabilizing the inner mitochondrial membrane potential and reducing the formation of ROS. The role of UCP2 in neuroprotection is still in debate. This study seeks to clarify the role of UCP2 in transient focal ischemia (tFI) and to further understand the mechanisms of ischemic brain damage. Both wild-type and UCP2-knockout mice were subjected to tFI. Knocking out UCP2 significantly increased the infarct volume to 61% per hemisphere as compared with 18% in wild-type animals. Knocking out UCP2 suppressed antioxidant, cell-cycle, and DNA repair genes, including Sod1 and Sod2, Gstm1, and cyclins. Furthermore, knocking out UCP2 significantly upregulated the protein levels of the inflammatory cytokines, including CTACK, CXCL16, Eotaxin-2, fractalkine, and BLC. It is concluded that knocking out the UCP2 gene exacerbates neuronal death after cerebral ischemia with reperfusion and this detrimental effect is mediated by alteration of antioxidant genes and upregulation of inflammatory mediators.

Original languageEnglish (US)
Pages (from-to)1825-1833
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume30
Issue number11
DOIs
StatePublished - Nov 2010

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Ischemia
Mitochondrial Membranes
Cytokines
Gene Expression
Reactive Oxygen Species
Chemokine CCL24
Brain
Antioxidants
Chemokine CX3CL1
Genes
Cyclins
Wild Animals
Mitochondrial Membrane Potential
Mitochondrial Proteins
Electron Transport
Brain Ischemia
Knockout Mice
DNA Repair
Reperfusion
Protons

Keywords

  • chemokines
  • MCAO
  • mitochondria
  • neuronal death
  • stroke
  • UCP

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines. / Haines, Bryan A.; Mehta, Suresh L.; Pratt, Serena M.; Warden, Craig H; Li, P. Andy.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 30, No. 11, 11.2010, p. 1825-1833.

Research output: Contribution to journalArticle

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