title: Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels.
abstract: Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca(2+) channels in HEK293 cells raised basal [Ca(2+)]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca(2+)]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca(2+) currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca(2+) channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically.
authors.affiliation: Division of Cardiovascular and Diabetes Research, LIGHT, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Duckles
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Boycott
authors.forename: Moza M
authors.initials: MM
authors.lastname: Al-Owais
authors.forename: Jacobo
authors.initials: J
authors.lastname: Elies
authors.forename: Emily
authors.initials: E
authors.lastname: Johnson
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dallas
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.forename: Francesca
authors.initials: F
authors.lastname: Giuntini
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Jason L
authors.initials: JL
authors.lastname: Scragg
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D049109:Cell Proliferation; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
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