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Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels
Duckles, H. Boycott, H.E. Al-Owais, M.M. Johnson, E. Dallas, M.L. Porter, K.E. Giuntini, F. Boyle, J.P. Scragg, J.L.
Duckles, H.
Boycott, H.E.
Al-Owais, M.M.
Johnson, E.
Dallas, M.L.
Porter, K.E.
Giuntini, F.
Boyle, J.P.
Scragg, J.L.
Publication Date
2015-02
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© The Author(s) 2014. This article is published with open access at
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This article is distributed under the terms of the Creative Commons Attribution License which
permits any use, distribution, and reproduction in any medium, provided the original author(s)
and the source are credited.
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openAccess
Accepted for publication
2014-03-14
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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 Ca2+ channels
in HEK293 cells raised basal [Ca2+]i and increased proliferation
as compared with non-transfected cells. Proliferation and
[Ca2+]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) Ca2+
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
Ca2+ channels. This signalling pathway provides a novel
means by which proliferation of VSMCs (and other cells)
may be regulated therapeutically.
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Published version
Citation
Duckles H, Boycott HE, Al-Owais MM et al (2015) Heme oxygenase-1 regulates cell
proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels. Pflügers Archiv –
European Journal of Physiology. 467(2): 415-427.
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Article