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Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Parfenova, Helena Basuroy, Shyamali Bhattacharya, Sujoy Tcheranova, Dilyara Qu, Yan Dong Regan, Raymond F. Leffler, Charles William |
| Copyright Year | 2006 |
| Abstract | In cerebral circulation, epileptic seizures associated with excessive release of the excitatory neurotransmitter glutamate cause endothelial injury. Heme oxygenase (HO), which metabolizes heme to a vasodilator, carbon monoxide (CO), and antioxidants, biliverdin/bilirubin, is highly expressed in cerebral microvessels as a constitutive isoform, HO-2, whereas the inducible form, HO-1, is not detectable. Using cerebral vascular endothelial cells from newborn pigs and HO-2-knockout mice, we addressed the hypotheses that 1) glutamate induces oxidative stress-related endothelial death by apoptosis, and 2) HO-1 and HO-2 are protective against glutamate cytotoxicity. In cerebral endothelial cells, glutamate (0.1-2.0 mM) increased formation of reactive oxygen species, including superoxide radicals, and induced major keystone events of apoptosis, such as NF-kappaB nuclear translocation, caspase-3 activation, DNA fragmentation, and cell detachment. Glutamate-induced apoptosis was greatly exacerbated in HO-2 gene-deleted murine cerebrovascular endothelial cells and in porcine cells with pharmacologically inhibited HO-2 activity. Glutamate toxicity was prevented by superoxide dismutase, suggesting apoptotic changes are oxidative stress related. When HO-1 was pharmacologically upregulated by cobalt protoporphyrin, apoptotic effects of glutamate in cerebral endothelial cells were completely prevented. Glutamate-induced reactive oxygen species production and apoptosis were blocked by a CO-releasing compound, CORM-A1 (50 microM), and by bilirubin (1 microM), consistent with the antioxidant and cytoprotective roles of the end products of HO activity. We conclude that both HO-1 and HO-2 have anti-apoptotic effects against oxidative stress-related glutamate toxicity in cerebral vascular endothelium. Although HO-1, when induced, provides powerful protection, HO-2 is an essential endogenous anti-apoptotic factor against glutamate toxicity in the cerebral vascular endothelium. |
| Starting Page | 471 |
| Ending Page | 471 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| DOI | 10.1152/ajpcell.00386.2005 |
| PubMed reference number | 16371440 |
| Journal | Medline |
| Volume Number | 290 |
| Issue Number | 5 |
| Alternate Webpage(s) | http://ajpcell.physiology.org/content/ajpcell/290/5/C1399.full.pdf |
| Journal | American journal of physiology. Cell physiology |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
