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This Article Full Text Full Text (PDF) All Versions of this Article: 291/5/H2493    most recent 01254.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Tharp, D. L. Articles by Bowles, D. K. Search for Related Content PubMed PubMed Citation Articles by Tharp, D. L. Articles by Bowles, D. K.

Upregulation of intermediate-conductance Ca²⁺-activated K⁺ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle

Departments of ¹Biomedical Sciences and ²Veterinary Pathobiology and ³Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri; and the ⁴Department of Molecular Physiology and Biological Physics and The Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia

Submitted 29 November 2005 ; accepted in final form 19 June 2006

A hallmark of smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and restenosis is suppression of SMC differentiation marker genes, proliferation, and migration. Blockade of intermediate-conductance Ca²⁺-activated K⁺ channels (IKCa1) has been shown to inhibit restenosis after carotid balloon injury in the rat; however, whether IKCa1 plays a role in SMC phenotypic modulation is unknown. Our objective was to determine the role of IKCa1 channels in regulating coronary SMC phenotypic modulation and migration. In cultured porcine coronary SMCs, platelet-derived growth factor-BB (PDGF-BB) increased TRAM-34 (a specific IKCa1 inhibitor)-sensitive K⁺ current 20-fold; increased IKCa1 promoter histone acetylation and c-jun binding; increased IKCa1 mRNA 4-fold; and potently decreased expression of the smooth muscle differentiation marker genes smooth muscle myosin heavy chain (SMMHC), smooth muscle -actin (SMA), and smoothelin-B, as well as myocardin. Importantly, TRAM-34 completely blocked PDGF-BB-induced suppression of SMMHC, SMA, smoothelin-B, and myocardin and inhibited PDGF-BB-stimulated migration by 50%. Similar to TRAM-34, knockdown of endogenous IKCa1 with siRNA also prevented the PDGF-BB-induced increase in IKCa1 and decrease in SMMHC mRNA. In coronary arteries from high fat/high cholesterol-fed swine demonstrating signs of early atherosclerosis, IKCa1 expression was 22-fold higher and SMMHC, smoothelin-B, and myocardin expression significantly reduced in proliferating vs. nonproliferating medial cells. Our findings demonstrate that functional upregulation of IKCa1 is required for PDGF-BB-induced coronary SMC phenotypic modulation and migration and support a similar role for IKCa1 in coronary SMC during early coronary atherosclerosis.

migration; atherosclerosis; activator protein-1; dedifferentaiation; KCNN4; KCa 3.1

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