title: Heme Oxygenase-1 Influences Apoptosis via CO-mediated Inhibition of K+ Channels.
abstract: Hypoxic/ischemic episodes can trigger oxidative stress-mediated loss of central neurons via apoptosis, and low pO2 is also a feature of the tumor microenvironment, where cancer cells are particularly resistant to apoptosis. In the CNS, ischemic insult increases expression of the CO-generating enzyme heme oxygenase-1 (HO-1), which is commonly constitutively active in cancer cells. It has been proposed that apoptosis can be regulated by the trafficking and activity of K(+) channels, particularly Kv2.1. We have explored the idea that HO-1 may influence apoptosis via regulation of Kv2.1. Overexpression of Kv2.1 in HEK293 cells increased their vulnerability to oxidant-induced apoptosis. CO (applied as the donor CORM-2) protected cells against apoptosis and inhibited Kv2.1 channels. Similarly in hippocampal neurones, CO selectively inhibited Kv2.1 and protected neurones against oxidant-induced apoptosis. In medulloblastoma sections we identified constitutive expression of HO-1 and Kv2.1, and in the medulloblastoma-derived cell line DAOY, hypoxic HO-1 induction or exposure to CO protected cells against apoptosis, and also selectively inhibited Kv2.1 channels expressed in these cells. These studies are consistent with a central role for Kv2.1 in apoptosis in both central neurones and cancer cells. They also suggest that HO-1 expression can strongly influence apoptosis via CO-mediated regulation of Kv2.1 activity.
authors: Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors: Moza M
authors: MM
authors: Al-Owais
authors: Mark L
authors: ML
authors: Dallas
authors: John P
authors: JP
authors: Boyle
authors: Jason L
authors: JL
authors: Scragg
authors: Chris
authors: C
authors: Peers
mesh_terms: D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000502:physiology*; D019610:Cytoprotection; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C496988:KCNB1 protein, human; D051669:Shab Potassium Channels; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1