Gene inactivation of Na+H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia

Yanping Wang, Jing Luo, Xinzhi Chen, Hai Chen, Sam W. Cramer, Dandan Sun

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

We investigated mechanisms underlying the Na+/H+ exchanger isoform 1 (NHE1)-mediated neuronal damage in transient focal ischemia. Physiological parameters, body and tympanic temperatures, and regional cerebral blood flow during 30 min of middle cerebral artery occlusion were similar in wild-type NHE1 (NHE1+/+) and NHE1 heterozygous (NHE1+/-) mice. NHE1+/ + mice developed infarct volume of 57.3 ± 8.8 mm>s.3 at 24 h reperfusion (Rp), which progressed to 86.1 ± 10.0 mm3 at 72 h Rp. This delayed cell death was preceded by release of mitochondrial cytochrome c (Cyt. C), nuclear translocation of apoptosis-inducing factor (AIF), activation of caspase-3, and TUNEL-positive staining and chromatin condensation in the ipsilateral hemispheres of NHE1 + /+ brains. In contrast, NHE1+/- mice had a significantly smaller infarct volume and improved neurological function. A similar neuroprotection was obtained with NHE1 inhibitor HOE 642. The number of apoptotic cells, release of AIF and Cyt. C or levels of active caspase-3 was significantly reduced in NHE1+7" brains. These data imply that NHE1 activity may contribute to ischemic apoptosis. Ischemic brains did not exhibit changes of NHE1 protein expression. In contrast, up-regulation of NHE1 expression was found in NHE1+/- neurons after in vitro ischemia. These data suggest that NHE1 activation following cerebral ischemia contributes to mitochondrial damage and ischemic apoptosis.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalEuropean Journal of Neuroscience
Volume28
Issue number1
DOIs
StatePublished - Jul 2008

Keywords

  • Apoptosis-inducing factor
  • Cytochrome c
  • HOE 642
  • Infarction
  • Neuronal death

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