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

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(3) at 24 h reperfusion (Rp), which progressed to 86.1 +/- 10.0 mm(3) 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+/- 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.

• Authors: Yanping Wang, Jing Luo, Xinzhi Chen, Hai Chen, Sam W Cramer, Dandan Sun
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 28 Issue 1 Pg. 51-61 (Jul 2008) ISSN: 1460-9568 [Electronic] France
• PMID: 18662334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cation Transport Proteins
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Protein Isoforms
• Slc9a1 protein, mouse
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers
• Cytochromes c
• Caspase 3

Topics

• Animals
• Apoptosis (physiology)
• Astrocytes (cytology, metabolism)
• Brain (cytology, metabolism)
• Brain Ischemia (metabolism, pathology)
• Caspase 3 (metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Cell Nucleus (metabolism)
• Cells, Cultured
• Cerebrovascular Circulation
• Cytochromes c (metabolism)
• Gene Silencing
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• In Situ Nick-End Labeling
• Mice
• Mice, Transgenic
• Mitochondria (metabolism, pathology)
• Neurons (cytology, physiology)
• Protein Isoforms (genetics, metabolism)
• Regional Blood Flow
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (genetics, metabolism)