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Am J Physiol Cell Physiol 290: C1399-C1410, 2006. First published December 21, 2005; doi:10.1152/ajpcell.00386.2005
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VASCULAR BIOLOGY

Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection

Helena Parfenova,1 Shyamali Basuroy,1 Sujoy Bhattacharya,1 Dilyara Tcheranova,1 Yan Qu,2 Raymond F. Regan,2 and Charles W. Leffler1

1Laboratory for Research in Neonatal Physiology, Department of Physiology, Vascular Biology Center, University of Tennessee Health Science Center, Memphis, Tennessee; and 2Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 1 August 2005 ; accepted in final form 19 December 2005

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-{kappa}B 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 µM), and by bilirubin (1 µM), 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.

endothelium; carbon monoxide; bilirubin; injury; reactive oxygen species; heme oxygenase


Address for reprint requests and other correspondence: H. Parfenova, Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163 (e-mail: hparf{at}physio1.utmem.edu)




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