HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells

Basuroy, Shyamali; Bhattacharya, Sujoy; Tcheranova, Dilyara; Qu, Yan; Regan, Raymond F.; Leffler, Charles W.; Parfenova, Helena

doi:10.1152/ajpcell.00032.2006

Cited by 104 publications

(110 citation statements)

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“…In cerebral vascular endothelial cells, no induction of HO-1 occurred in response to prolonged stimulation (10-24h) by potent pro-oxidants, including arachidonic acid, the inflammatory cytokine, tumor necrosis factor α (TNFα), or the excitatory neuromediator, glutamate [40,44,45]. Furthermore, neither the NO donors SIN-1 (3-morpholinosydnonimine) and SNAP (S-nitroso-N-acetylpenicillamine), strong pro-oxidants, nor the endoplasmic reticulum stress signal, thapsigargin, upregulated HO-1 expression [45].…”

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%

“…Among metalloporphyrins, only cobalt protoporphyrin (CoPP, 10 -5 M), and, to a much lesser extent, hemin (10 -4 M) induced HO-1 in cerebral vascular endothelial cells and in astrocytes from newborn pigs within 14-24h [39,40,44,45]. In contrast, other metalloporphyrins, SnPP and ZnPP, and transition metals (CoCl 2 , FeCl 2 , FeCl 3 ) over a wide concentration range (up to 10 -4 M) did not upregulate HO-1 in cerebrovascular endothelial cells [45].…”

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%

“…In contrast, other metalloporphyrins, SnPP and ZnPP, and transition metals (CoCl 2 , FeCl 2 , FeCl 3 ) over a wide concentration range (up to 10 -4 M) did not upregulate HO-1 in cerebrovascular endothelial cells [45]. Pharmacological intervention with CoPP has been successfully used to induce HO-1 expression in the brain, cerebral vessels, and cerebrovascular endothelial cells and to investigate brain HO-1 functions in vivo and in vitro [39,40,44]. Induction of HO-1 protein and an overall increase in HO activity in the brain and cerebral vessels was produced 24 h after systemic administration of CoPP to newborn pigs (20 mg/kg ip) [39].…”

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%

“…Brain TNFα production is increased during seizures and contributes to neuronal death [122,125,126]. TNFα also directly targets the cerebral vasculature [44]. In cerebral vascular endothelial cells from newborn pigs and adult rats, TNFα increases ROS formation and causes oxidative-stress-mediated apoptosis [44].…”

Section: Seizures Neuronal Injury and Cerebral Vascular Functionmentioning

confidence: 99%

“…Brain endothelium is highly susceptible to injury caused by the pro-inflammatory mediator, TNFα, abundantly produced by injured brain. In porcine and murine cerebral vascular endothelial cells, TNFα is a potent pro-oxidant and proapoptotic signal that induces key events of apoptosis within 1-3h [44]. NADPH oxidase is identified as the major superoxide-producing enzyme in cerebral vascular endothelial cells that is immediately activated by the cytokine and initiates a signaling cascade leading to apoptosis [134].…”

Section: Ho-2 Protection Against Inflammation-induced Endothelial mentioning

confidence: 99%

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Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%