Abstract
The intermediate conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis, and vascular remodeling. We examined the electrophysiological and transcriptional mechanisms by which KCa3.1 regulates vascular smooth muscle cell (VSMC) proliferation. Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i. KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP-response element-binding protein (CREB), c-Fos, and neuron-derived orphan receptor-1 (NOR-1). This antiproliferative effect was abolished by elevating [Ca(2+)]i. KCa3.1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-Fos, and NOR-1. Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by abolishing the expression and activity of KCa3.1 and PDGF β-receptors and inhibiting the rise in [Ca(2+)]i. The stimulation also attenuated the levels of phosphorylated CREB, c-Fos, and cyclin expression. After KCa3.1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3.1 stimulation induced a spindle-shaped cellular appearance, with low l-caldesmon and high calponin-1. In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways, and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis.
Highlights
The mechanism by which KCa3.1 regulates cell proliferation remains elusive
We examined the effect of pharmacological KCa3.1 blockade or activation, gene silencing, or overexpression on platelet-derived growth factor-BB (PDGF)-induced proliferation of vascular smooth muscle cells (VSMCs), focusing on changes in [Ca2ϩ]i, activation of mitogenic signaling pathways, cell cycle progression, morphology, and phenotypic characteristics in human coronary artery VSMCs (HCSMCs)
KCa3.1 Regulates Cell Cycle Progression—We studied the effect of TRAM-34 or EBIO treatment on the activation of cAMP-response element-binding protein (CREB) and on the expression of c-Fos, two factors playing an important role in Platelet-derived growth factor-BB (PDGF)-induced VSMC proliferation [32, 35]
Summary
The mechanism by which KCa3.1 regulates cell proliferation remains elusive. Results: KCa3.1 regulates the expression of transcription factors and cyclins by controlling intracellular calcium levels in activated vascular smooth muscle cells (VSMCs). KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca2؉]i and attenuating the expression of phosphorylated cAMP-response element-binding protein (CREB), c-Fos, and neuron-derived orphan receptor-1 (NOR-1). This antiproliferative effect was abolished by elevating [Ca2؉]i. We hypothesized that KCa3.1 blockade or knockdown would suppress VSMC proliferation by inhibiting the mitogen-induced rise in [Ca2ϩ]i and subsequent mitogenic signaling pathways, whereas KCa3.1 stimulation or overexpression would confer the opposite effects To test this hypothesis, we examined the effect of pharmacological KCa3.1 blockade or activation, gene silencing, or overexpression on platelet-derived growth factor-BB (PDGF)-induced proliferation of VSMCs, focusing on changes in [Ca2ϩ]i, activation of mitogenic signaling pathways, cell cycle progression, morphology, and phenotypic characteristics in human coronary artery VSMCs (HCSMCs)
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