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1 Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri, United States
2 Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, United States; The Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States
3 Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri, United States; Veterinary Pathobiology, University of Missouri-Columbia, Columbia, Missouri, United States
4 Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri, United States; Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, United States
* To whom correspondence should be addressed. E-mail: bowlesd{at}missouri.edu.
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 following 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, 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 versus non-proliferating 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.
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