title: Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway.
abstract: Phenotypic modulation (PM) of vascular smooth muscle cells (VSMCs) is central to the process of intimal hyperplasia which constitutes a common pathological lesion in occlusive vascular diseases. Changes in the functional expression of Kv1.5 and Kv1.3 currents upon PM in mice VSMCs have been found to contribute to cell migration and proliferation. Using human VSMCs from vessels in which unwanted remodeling is a relevant clinical complication, we explored the contribution of the Kv1.5 to Kv1.3 switch to PM. Changes in the expression and the functional contribution of Kv1.3 and Kv1.5 channels were studied in contractile and proliferating VSMCs obtained from human donors. Both a Kv1.5 to Kv1.3 switch upon PM and an anti-proliferative effect of Kv1.3 blockers on PDGF-induced proliferation were observed in all vascular beds studied. When investigating the signaling pathways modulated by the blockade of Kv1.3 channels, we found that anti-proliferative effects of Kv1.3 blockers on human coronary artery VSMCs were occluded by selective inhibition of MEK/ERK and PLCγ signaling pathways, but were unaffected upon blockade of PI3K/mTOR pathway. The temporal course of the anti-proliferative effects of Kv1.3 blockers indicates that they have a role in the late signaling events essential for the mitogenic response to growth factors. These findings establish the involvement of Kv1.3 channels in the PM of human VSMCs. Moreover, as current therapies to prevent restenosis rely on mTOR blockers, our results provide the basis for the development of novel, more specific therapies.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Edificio IBGM, c/ Sanz y Forés s/n, 47003, Valladolid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Cidad
authors.forename: Eduardo
authors.initials: E
authors.lastname: Miguel-Velado
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz-McDavitt
authors.forename: Esperanza
authors.initials: E
authors.lastname: Alonso
authors.forename: Laura
authors.initials: L
authors.lastname: Jiménez-Pérez
authors.forename: Agustín
authors.initials: A
authors.lastname: Asuaje
authors.forename: Yamila
authors.initials: Y
authors.lastname: Carmona
authors.forename: Daniel
authors.initials: D
authors.lastname: García-Arribas
authors.forename: Javier
authors.initials: J
authors.lastname: López
authors.forename: Yngrid
authors.initials: Y
authors.lastname: Marroquín
authors.forename: Mirella
authors.initials: M
authors.lastname: Fernández
authors.forename: Mercè
authors.initials: M
authors.lastname: Roqué
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pérez-García
authors.forename: José Ramón
authors.initials: JR
authors.lastname: López-López
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: C496973:KCNA3 protein, human; C496981:KCNA5 protein, human; D051664:Kv1.3 Potassium Channel; D051666:Kv1.5 Potassium Channel; D010726:Phosphodiesterase Inhibitors; D010982:Platelet-Derived Growth Factor; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases