title: Laminar shear stress upregulates endothelial Ca²⁺-activated K⁺ channels KCa2.3 and KCa3.1 via a Ca²⁺/calmodulin-dependent protein kinase kinase/Akt/p300 cascade.
abstract: In endothelial cells (ECs), Ca²⁺-activated K⁺ channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca²⁺ levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca²⁺/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca²⁺/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm²) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8-30), whereas oscillatory shear (OS; ± 5 dyn/cm² × 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada;
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.forename: Alexandra
authors.initials: A
authors.lastname: Santu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zheng
authors.forename: Sang Don
authors.initials: SD
authors.lastname: Koh
authors.forename: Masanori
authors.initials: M
authors.lastname: Ohta
authors.forename: Linda M
authors.initials: LM
authors.lastname: Filimban
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemaître
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Teraoka
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
mesh_terms: D000222:Adaptation, Physiological; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D006439:Hemodynamics; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008564:Membrane Potentials; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C406328:KCNN3 protein, human; C496923:KCNN4 protein, human; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051057:Proto-Oncogene Proteins c-akt; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase
keywords: Ca2+-dependent signaling; circulation; endothelial function; ion channels