The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1
Pathological proliferation of vascular smooth muscle cells (VSMC) is a central feature of vascular disorders such as atherosclerosis and restenosis. During such proliferative conditions the expression of the T-type Ca2+ channel is increased, providing an important route for Ca2+ entry. The inducible...
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ndltd-bl.uk-oai-ethos.bl.uk-6780442017-10-04T03:31:08ZThe vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1Duckles, HayleyPeers, Chris2013Pathological proliferation of vascular smooth muscle cells (VSMC) is a central feature of vascular disorders such as atherosclerosis and restenosis. During such proliferative conditions the expression of the T-type Ca2+ channel is increased, providing an important route for Ca2+ entry. The inducible stress-response protein, heme oxygenase-1 (HO-1), is also up-regulated during vascular disorders. This enzyme confers cytoprotective effects via the breakdown of free heme to produce iron, biliverdin, and carbon monoxide (CO). CO has been shown to be anti-inflammatory, anti-apoptotic, and anti-proliferative at low concentrations. Furthermore, CO is emerging as a modulator of various ion channels, and our research group has recently found that CO inhibits the T-type Ca2+ current via whole-cell patch clamp recordings. Therefore, the aim of this thesis was to investigate whether the VSMC T-type Ca2+ channel could act as an anti-proliferative target for HO-1-derived CO. HEK293 cells over-expressing the Cav3.2 T-type Ca2+ channel produced higher basal [Ca2+]i and displayed an augmented proliferative response. [Ca2+]i and proliferation were both reduced by T-type Ca2+ channel inhibition, CO exposure, and HO-1 induction. T-type Ca2+ channel inhibition and HO-1 induction reduced [Ca2+]i and proliferation in the rat aortic VSMC line, A7r5. Exogenous CO exposure decreased [Ca2+]i in A7r5 cells, but conferred insignificant anti-proliferative effects, which correlated to a relatively low expression of the T-type Ca2+ channel. T-type Ca2+ channel inhibition, CO exposure, and HO-1 induction all have anti-proliferative effects in human VSMCs, yet simultaneous HO-1 induction and T-type Ca2+ channel inhibition do not cause additive inhibitory effects on proliferation. These data provide evidence that CO is anti-proliferative, and that CO potentially acts via the T-type Ca2+ channel. This pathway could be a novel therapeutic target for vascular disorders involving excessive smooth muscle cell proliferation.610University of Leedshttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678044http://etheses.whiterose.ac.uk/4846/Electronic Thesis or Dissertation |
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610 Duckles, Hayley The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
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Pathological proliferation of vascular smooth muscle cells (VSMC) is a central feature of vascular disorders such as atherosclerosis and restenosis. During such proliferative conditions the expression of the T-type Ca2+ channel is increased, providing an important route for Ca2+ entry. The inducible stress-response protein, heme oxygenase-1 (HO-1), is also up-regulated during vascular disorders. This enzyme confers cytoprotective effects via the breakdown of free heme to produce iron, biliverdin, and carbon monoxide (CO). CO has been shown to be anti-inflammatory, anti-apoptotic, and anti-proliferative at low concentrations. Furthermore, CO is emerging as a modulator of various ion channels, and our research group has recently found that CO inhibits the T-type Ca2+ current via whole-cell patch clamp recordings. Therefore, the aim of this thesis was to investigate whether the VSMC T-type Ca2+ channel could act as an anti-proliferative target for HO-1-derived CO. HEK293 cells over-expressing the Cav3.2 T-type Ca2+ channel produced higher basal [Ca2+]i and displayed an augmented proliferative response. [Ca2+]i and proliferation were both reduced by T-type Ca2+ channel inhibition, CO exposure, and HO-1 induction. T-type Ca2+ channel inhibition and HO-1 induction reduced [Ca2+]i and proliferation in the rat aortic VSMC line, A7r5. Exogenous CO exposure decreased [Ca2+]i in A7r5 cells, but conferred insignificant anti-proliferative effects, which correlated to a relatively low expression of the T-type Ca2+ channel. T-type Ca2+ channel inhibition, CO exposure, and HO-1 induction all have anti-proliferative effects in human VSMCs, yet simultaneous HO-1 induction and T-type Ca2+ channel inhibition do not cause additive inhibitory effects on proliferation. These data provide evidence that CO is anti-proliferative, and that CO potentially acts via the T-type Ca2+ channel. This pathway could be a novel therapeutic target for vascular disorders involving excessive smooth muscle cell proliferation. |
author2 |
Peers, Chris |
author_facet |
Peers, Chris Duckles, Hayley |
author |
Duckles, Hayley |
author_sort |
Duckles, Hayley |
title |
The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
title_short |
The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
title_full |
The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
title_fullStr |
The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
title_full_unstemmed |
The vascular smooth muscle T-type Ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
title_sort |
vascular smooth muscle t-type ca2+ channel : an anti-proliferative target for heme oxygenase-1 |
publisher |
University of Leeds |
publishDate |
2013 |
url |
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678044 |
work_keys_str_mv |
AT duckleshayley thevascularsmoothmusclettypeca2channelanantiproliferativetargetforhemeoxygenase1 AT duckleshayley vascularsmoothmusclettypeca2channelanantiproliferativetargetforhemeoxygenase1 |
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