Laura Cobeno
Complutense University of Madrid
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Featured researches published by Laura Cobeno.
Circulation Research | 2006
Angel Cogolludo; Laura Moreno; Federica Lodi; Giovanna Frazziano; Laura Cobeno; Juan Tamargo; Francisco Perez-Vizcaino
Multiple lines of evidence indicate that serotonin (5-hydroxytryptamine [5-HT]) and voltage-gated K+ (KV) channels play a central role in the pathogenesis of pulmonary hypertension (PH). We hypothesized that 5-HT might modulate the activity of KV channels, therefore establishing a link between these pathogenetic factors in PH. Here, we studied the effects of 5-HT on KV channels present in rat pulmonary artery smooth muscle cells (PASMC) and on hKV1.5 channels stably expressed in Ltk− cells. 5-HT reduced native KV and hKV1.5 currents, depolarized cell membrane, and caused a contraction of isolated pulmonary arteries. The effects of 5-HT on KV currents and contraction were markedly prevented by the 5-HT2A receptor antagonist ketanserin. Incubation with inhibitors of phospholipase C (U73122), classic protein kinase Cs (Gö6976), or tyrosine kinases (genistein and tyrphostin 23), the cholesterol depletion agent β-cyclodextrin or concanavalin A, an inhibitor of endocytotic processes, also prevented the effects of 5-HT. In homogenates from pulmonary arteries, 5-HT2A receptors and caveolin-1 coimmunoprecipitated with KV1.5 channels, and this was increased on stimulation with 5-HT. Moreover, KV1.5 channels were internalized when cells were stimulated with 5-HT, and this was prevented by concanavalin A. These findings indicate that activation of 5-HT2A receptors inhibits native KV and hKV1.5 currents via phospholipase C, protein kinase C, tyrosine kinase, and a caveolae pathway. KV channel inhibition accounts, at least partly, for 5-HT-induced pulmonary vasoconstriction and might play a role in PH.
Annals of the New York Academy of Sciences | 2006
Angel Cogolludo; Giovanna Frazziano; Laura Cobeno; Laura Moreno; Federica Lodi; Eduardo Villamor; Juan Tamargo; Francisco Perez-Vizcaino
Abstract:u2002 Voltage‐gated potassium channels (Kv) and thromboxane A2 (TXA2) have been involved in several forms of human and experimental pulmonary hypertension. We have reported that the TXA2 analog U46619, via activation of TP receptors and PKCζ, inhibited Kv currents in rat pulmonary artery smooth muscle cells (PASMC), increased cytosolic calcium, and induced a contractile response in isolated rat and piglet pulmonary arteries (PA). Herein, we have analyzed the role of reactive oxygen species (ROS) in this signaling pathway. In rat PA, U46619 increased dichlorofluorescein fluorescence, an indicator of intracellular hydrogen peroxide, and this effect was prevented by the NADPH oxidase inhibitor apocynin and by polyethyleneglycol‐catalase (PEG‐catalase, a membrane‐permeable form of catalase). U46619 inhibited Kv currents in native PASMC and these effects were strongly inhibited by apocynin. The contractile responses to U46619 in isolated PA were inhibited by PEG‐catalase and the NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin. A membrane permeable of hydrogen peroxide, t‐butyl hydroperoxide, also inhibited Kv currents and induced a contractile response. Activation of NADPH oxidase and the subsequent production of hydrogen peroxide are involved in the Kv channel inhibition and the contractile response induced by TP receptor activation in rat PA.
Molecular Pharmacology | 2007
Laura Moreno; Giovanna Frazziano; Angel Cogolludo; Laura Cobeno; Juan Tamargo; Francisco Perez-Vizcaino
Voltage-gated potassium (KV) channels play an essential role in regulating pulmonary artery function, and they underpin the phenomenon of hypoxic pulmonary vasoconstriction. Pulmonary hypertension is characterized by inappropriate vasoconstriction, vascular remodeling, and dysfunctional KV channels. In the current study, we aimed to elucidate the role of PKCζ and its adaptor protein p62 in the modulation of KV channels. We report that the thromboxane A2 analog 9,11-dideoxy-11α,9α-epoxymethano-prostaglandin F2α methyl acetate (U46619) inhibited KV currents in isolated mice pulmonary artery myocytes and the KV current carried by human cloned KV1.5 channels expressed in Ltk– cells. Using protein kinase C (PKC)ζ–/– and p62–/– mice, we demonstrate that these two proteins are involved in the KV channel inhibition. PKCζ coimmunoprecipitated with KV1.5, and this interaction was markedly reduced in p62–/– mice. Pulmonary arteries from PKCζ–/– mice also showed a diminished [Ca2+]i and contractile response, whereas genetic inactivation of p62–/– resulted in an absent [Ca2+]i response, but it preserved contractile response to U46619. These data demonstrate that PKCζ and its adaptor protein p62 play a key role in the modulation of KV channel function in pulmonary arteries. These observations identify PKCζ and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension.
Cardiovascular Research | 2007
Angel Cogolludo; Giovanna Frazziano; Ana M. Briones; Laura Cobeno; Laura Moreno; Federica Lodi; Mercedes Salaices; Juan Tamargo; Francisco Perez-Vizcaino
The FASEB Journal | 2008
Laura Cobeno; Eduardo Villamor; Angel Cogolludo; Giovanna Frazziano; Javier Moral; Bea Zoer; Laura Moreno; Francisco Perez-Vizcaino
The FASEB Journal | 2007
Giovanna Frazziano; Angel Cogolludo; Laura Moreno; Federica Lodi; Laura Cobeno; Juan Tamargo; Francisco Perez-Vizcaino
The FASEB Journal | 2007
Angel Cogolludo; Pia Ågren; Saskia van der Sterren; Carlos E Blanco; Laura Cobeno; Giovanna Frazziano; Francisco Perez-Vizcaino; Eduardo Villamor
The FASEB Journal | 2008
Giovanna Frazziano; Laura Cobeno; Angel Cogolludo; Laura Moreno; Javier Moral; Eduardo Villamor; Francisco Perez-Vizcaino
The FASEB Journal | 2008
Angel Cogolludo; Laura Moreno; Laura Cobeno; Giovanna Frazziano; Javier Castañeda; C. Gonzalez; Eduardo Villamor; Francisco Perez-Vizcaino
The FASEB Journal | 2008
Ana M. Briones; Laura Cobeno; Alessandra Simão Padilha; Angel Cogolludo; Dalton Valentim Vassallo; Francisco Perez-Vizcaino; Mercedes Salaices