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GROWTH, DIFFERENTIATION, AND APOPTOSIS
in cerebral vascular endothelial cells
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 25 January 2006 ; accepted in final form 30 June 2006
Tumor necrosis factor-
(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, 15 ng/ml TNF- alone, or with 10 µg/ml cycloheximide (CHX) 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 wild-type mice. TNF- increased reactive oxygen species 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 cobalt portophyrin), TNF- did not cause apoptosis. A CO-releasing compound, CORM-A1, and bilirubin blocked TNF--induced reactive oxygen species accumulation and apoptosis consistent with the antioxidant and antiapoptotic roles of the end products of HO activity. We conclude that HO-2 is critical for protection of cerebrovascular endothelium against apoptotic changes induced by oxidative stress and cytokine-mediated inflammation.
carbon monoxide; bilirubin; vascular injury; reactive oxygen species; heme oxygenase; cycloheximide
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