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

Abstract

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 Ca(2+)-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 approximately 4-fold; and potently decreased expression of the smooth muscle differentiation marker genes smooth muscle myosin heavy chain (SMMHC), smooth muscle alpha-actin (SMalphaA), and smoothelin-B, as well as myocardin. Importantly, TRAM-34 completely blocked PDGF-BB-induced suppression of SMMHC, SMalphaA, smoothelin-B, and myocardin and inhibited PDGF-BB-stimulated migration by approximately 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.

Transforming Growth Factor-β1 (TGF-β1) Utilizes Distinct Pathways for the Transcriptional Activation of MicroRNA 143/145 in Human Coronary Artery Smooth Muscle Cells

“…These results are consistent with the sustained expression of miR145 following TGF-␤1 treatment versus only transient MYOCD mRNA induction. Clearly, the transcriptional and post-transcriptional regulation of MYOCD mRNA warrants deep analysis to uncover its positive regulation by TGF-␤1 as well as its well known reduction in expression under conditions of SMC phenotypic adaptation (4,55,56).…”

KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells

“…Upregulation of K Ca 3.1 channels has been found to promote excessive VSMC proliferation and migration induced by either mitogens (platelet-derived growth factor and EGF) or balloon catheter injury. [13][14][15] However, it is unknown whether AGEs is involved in the K Ca 3.1 channel regulation. In the present study, we demonstrated that AGE-BSA increased K Ca 3.1 current density and enhanced K Ca 3.1 channel protein expression in AGEs and K Ca 3.1 channels Li-Mei Zhao et al cultured rat VSMCs.…”

“…K Ca 3.1 channels are the predominant Ca 2 þ -activated K þ channels in proliferative smooth muscle cells but not in mature contractile cells. [11][12][13][14] The expression of K Ca 3.1 channels is increased in VSMCs in coronary arteries from patients and in aortas of ApoE À / À mice with atherogenesis, and K Ca 3.1 channel blocker markedly slows down the development of atherosclerosis in ApoE À / À mice. 16 However, reports related to the regulation of K Ca 3.1 channels are limited in diabetes.…”

“…[11][12][13][14] Inhibition of K Ca 3.1 channels by the selective blocker TRAM-34 is found to inhibit proliferation mediated by plateletderived growth factor in VSMCs and decrease the development of restenosis. 15 Local delivery of TRAM-34 via balloon catheter prevents ion channel phenotype switching (K Ca 1.1 to K Ca 3.1) in VSMCs of coronary artery and reduces subsequent restenosis.…”

“…15 Local delivery of TRAM-34 via balloon catheter prevents ion channel phenotype switching (K Ca 1.1 to K Ca 3.1) in VSMCs of coronary artery and reduces subsequent restenosis. 14 Moreover, Toyama et al 16 have provided the additional evidence that upregulation of K Ca 3.1 channels is related to atherogenesis in mice and humans.…”