Functional Regulation of ClC-3 in the migration of vascular smooth muscle cells

Sindura B Ganapathi; Shun-Guang Wei; Angelika Zaremba; Fred S Lamb; Stephen B Shears

doi:10.1161/HYPERTENSIONAHA.112.194209

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Functional Regulation of ClC-3 in the migration of vascular smooth muscle cells

Journal article

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Peer reviewed

Functional Regulation of ClC-3 in the migration of vascular smooth muscle cells

Sindura B Ganapathi, Shun-Guang Wei, Angelika Zaremba, Fred S Lamb and Stephen B Shears

Hypertension (Dallas, Tex. 1979), Vol.61(1), pp.174-179

01/2013

DOI: 10.1161/HYPERTENSIONAHA.112.194209

PMCID: PMC3521842

PMID: 23150504

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Abstract

Migration of vascular smooth muscle cells (VSMC) into neointima contributes to atherosclerosis and restenosis. This migration requires co-ordinated plasmalemmal fluxes of water and ions. Here, we show that aortic VSMC migration is dependent upon the regulation of transmembrane Cl − flux by ClC-3, a Cl − channel/transporter. The contribution of ClC-3 to plasmalemmal Cl − current was studied in VSMC by electrophysiological recordings. Cl − current was negligible in cells perfused with zero [Ca 2+ ]. Raising intracellular [Ca 2+ ] to 0.5 μM activated a Cl − current (I Cl.Ca ), approximately half of which was eliminated upon inhibition by KN-93 of calmodulin-dependent protein kinase II (CaMKII). I Cl.Ca was also halved by inositol-3,4,5,6-tetrakisphosphate (IP4), a cellular signal with the biological function of specifically preventing CaMKII from activating I Cl.Ca . Gene disruption of ClC-3 reduced I Cl.Ca by 50%. Moreover, I Cl.Ca in the ClC-3 null VSMC was not affected by either KN-93 or IP4. We conclude that I Cl.Ca comprises two components: one is ClC-3 independent, while the other is ClC-3 dependent, activated by CaMKII, and inhibited by IP4. We also assayed VSMC migration in transwell assays. Migration was halved in ClC-3 null cells versus wild-type cells. Additionally, inhibition of ClC-3 by either niflumic acid, KN-93 or IP4, each reduced cell-migration in wild-type cells, but not in ClC-3 null cells. These cell-signaling roles of ClC-3 in VSMC migration suggest new therapeutic approaches to vascular remodeling diseases.

atherosclerosis

chloride

restenosis

calcium

CaMKII

inositolphosphate

Details

Title: Subtitle: Functional Regulation of ClC-3 in the migration of vascular smooth muscle cells
Creators: Sindura B Ganapathi - Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA
Shun-Guang Wei - Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA
Angelika Zaremba - Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA
Fred S Lamb - Department of Pediatrics, University of Iowa Children’s Hospital, Iowa City, Iowa 52242, USA
Stephen B Shears - Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.61(1), pp.174-179
DOI: 10.1161/HYPERTENSIONAHA.112.194209
PMID: 23150504
PMCID: PMC3521842
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Grant note: ZIA ES080046-24 || ES / National Institute of Environmental Health Sciences : NIEHS
Language: English
Date published: 01/2013
Academic Unit: Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984065490202771

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