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in cerebral vascular endothelial cells
1 Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States
2 Emergency Medicine, Thomas Jefferson University, Philadelphia, United States
* To whom correspondence should be addressed. E-mail: sbasuroy{at}physio1.utmem.edu.
Tumor necrosis factor-alpha (TNF
) causes oxidative stress and apoptosis in a variety of cell types. Heme oxygenase (HO) degrades heme to bilirubin, an antioxidant, and carbon monoxide (CO), a cell cycle modulator and a vasodilator. Newborn pig cerebral microvascular endothelial cells (CMVEC) highly express constitutive HO-2. We investigated the role of HO-2 in protection against TNF-induced apoptosis in cerebral vascular endothelium. In CMVEC from mice and newborn pigs, TNF (15 ng/ml) alone, or with cycloheximide (CHX, 10 µg/ml) caused apoptosis detected by nuclear translocation of p65 NF
B, caspase-3 activation, DNA fragmentation, cell-cell contact destabilization, and cell detachment. TNF did not induce HO-1 expression in CMVEC. CMVEC from HO-2 knockout mice showed greater sensitivity to apoptosis caused by serum deprivation and TNF than did WT mice. TNF increased reactive oxygen species (ROS) generation, including hydrogen peroxide and superoxide radicals, as detected by dihydrorhodamine 123 and dihydroethidium. The TNF response was inhibited by superoxide dismutase and catalase suggesting apoptosis is oxidative stress-related. Inhibition of endogenous HO-2 in newborn pig CMVEC increased oxidative stress and exaggerated apoptosis caused by serum deprivation and TNF. In HO-1-overexpressing CMVEC (HO-1 selective induction by CoPP) TNF did not cause apoptosis. A CO-releasing compound, CORM-A1, and bilirubin blocked TNF-induced ROS accumulation and apoptosis consistent with the anti-oxidant and anti-apoptotic roles of the end products of HO activity. We conclude that HO-2 is critical for immediate protection of cerebrovascular endothelium against apoptotic changes induced by oxidative stress and cytokine-mediated inflammation.
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