Cerebroprotective Functions of HO-2

Abstract

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

Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

“…1 Endogenously produced CO has cytoprotective functions in the cardiovascular system that include antiapoptotic, antioxidant, and antiinflammatory influences. [1][2][3][4][5] Gaseous CO, administered at low concentrations, provides an effective treatment for diseases characterized by oxidative stress and inflammation. 1,5 The effects of gaseous CO can be reproduced by CO donors, termed CO-releasing molecules (CORMs).…”

“…5 In the cerebral circulation, endogenously produced CO is a physiologically relevant dilator regulator of cerebral blood flow, 6 and a potent antioxidant and antiapoptotic compound. 3,7,8 Previously, we have showed that CORM-A1 [Na 2 (H 3 BCO 2 )], a water-soluble compound that slowly releases gaseous CO in physiologic solutions, is a convenient tool to investigate the biologic effects of CO in in vivo and in vitro studies related to the mechanism of cerebral vascular survival during oxidative stress and inflammation. 3,8,9 CORM-A1 reduces formation of reactive oxygen species, prevents apoptosis, and promotes survival of cerebral vascular endothelial cells exposed to the excitotoxic neurotransmitter glutamate and a proinflammatory cytokine TNF-α.…”

“…3,7,8 Previously, we have showed that CORM-A1 [Na 2 (H 3 BCO 2 )], a water-soluble compound that slowly releases gaseous CO in physiologic solutions, is a convenient tool to investigate the biologic effects of CO in in vivo and in vitro studies related to the mechanism of cerebral vascular survival during oxidative stress and inflammation. 3,8,9 CORM-A1 reduces formation of reactive oxygen species, prevents apoptosis, and promotes survival of cerebral vascular endothelial cells exposed to the excitotoxic neurotransmitter glutamate and a proinflammatory cytokine TNF-α. 3,4 Oxidative stress-related apoptosis of cerebral endothelial cells leading to endothelial injury and cerebral vascular dysfunction is a devastating consequence of neonatal epileptic seizures.…”

“…3,8,9 CORM-A1 reduces formation of reactive oxygen species, prevents apoptosis, and promotes survival of cerebral vascular endothelial cells exposed to the excitotoxic neurotransmitter glutamate and a proinflammatory cytokine TNF-α. 3,4 Oxidative stress-related apoptosis of cerebral endothelial cells leading to endothelial injury and cerebral vascular dysfunction is a devastating consequence of neonatal epileptic seizures. 3,4,8,10 Adverse cerebral vascular outcome of seizures may cause or aggravate neuronal damage.…”

“…3,4 Oxidative stress-related apoptosis of cerebral endothelial cells leading to endothelial injury and cerebral vascular dysfunction is a devastating consequence of neonatal epileptic seizures. 3,4,8,10 Adverse cerebral vascular outcome of seizures may cause or aggravate neuronal damage. Prevention of cerebral vascular dysfunction may translate into prevention of the neonatal encephalopathy caused by seizures.…”