Person: Cogolludo Torralba, Ángel Luis
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First Name
Ángel Luis
Last Name
Cogolludo Torralba
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
6 results
Search Results
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Item Kv7 channels critically determine coronary artery reactivity: left-right differences and down-regulation by hyperglycaemia(Cardiovascular Research, 2015) Morales Cano, Daniel; Moreno Gutiérrez, Laura; Barreira, Bianca; Pandolfi, Rachele; Chamorro, Virginia; Jimenez, Rosario; Villamor, Eduardo; Duarte, Juan; Pérez Vizcaíno, Francisco; Cogolludo Torralba, Ángel LuisAims Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes. Methods and results We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabetic rats. Conclusion Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone.Item Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension(American Journal of Respiratory Cell and Molecular Biology, 2023) Vera Zambrano, Alba; Morales Cano, Daniel; Villegas Esguevillas, Marta; Cruz Utrilla, Alejandro; Fernández Malavé, Edgar Gonzalo; Escribano Subías, María Pilar; Pérez Vizcaíno, Francisco; Cogolludo Torralba, Ángel LuisReduced expression and/or activity of Kv1.5 channels (encoded byKCNA5) is a common hallmark in human or experimentalpulmonary arterial hypertension (PAH). Likewise, genetic variantsinKCNA5have been found in patients with PAH, but theirfunctional consequences and potential impact on the disease arelargely unknown. Herein, this study aimed to characterize thefunctional consequences of sevenKCNA5variants found in a cohortof patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type ormutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocalmicroscopy techniques were used for measuring protein expressionand cell apoptosis in HEK293 and human pulmonary artery smoothmuscle cells.KCNA5variants (namely, Arg184Pro and Gly384Arg)found in patients with PAH resulted in a clear loss of potassiumchannel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in apronounced reduction of Kv1.5 expression. Transfection withArg184Pro or Gly384Arg variants decreased apoptosis ofhuman pulmonary artery smooth muscle cells compared withthe wild-type cells, demonstrating thatKCNA5dysfunction inboth variants affects cell viability. Thus, in addition toaffecting channel activity, both variants were associated withimpaired apoptosis, a crucial process linked to the disease. Theestimated prevalence of dysfunctionalKCNA5variants in thePAH population analyzed was around 1%. The data indicatethat someKCNA5variants found in patients with PAH havecritical consequences for channel function, supporting the ideathatKCNA5pathogenic variants may be a causative orcontributing factor for PAH.Item Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model(Front. Pharmacol, 2023) Morales-Cano, Daniel; Barreira, Bianca; Pandolfi, Rachele; Villa-Valverde, Palmira; Izquierdo García, José Luis; Esquivel Ruiz, Sergio Antonio; Callejo Arranz, María; Rodríguez Ramírez De Arellano, Ignacio; Cogolludo Torralba, Ángel Luis; Ruiz-Cabello Osuna, Jesús; Pérez Vizcaíno, Francisco; Moreno Gutiérrez, LauraBackground: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit. Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods. Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA. Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.Item Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries(Clinical Science, 2016) Morales Cano, Daniel; Moreno Gutiérrez, Laura; Barreira, Bianca; Pandolfi, Rachele; Moral Sanz, Javier; Callejo Arranz, María; Mondejar Parreño, Gema; Pérez Vizcaíno, Francisco; Cogolludo Torralba, Ángel LuisPPARβ/δ activation protects against endothelial dysfunction in diabetic models. Elevated glucose is known to impair cAMP-induced relaxation and Kv channel function in coronary arteries (CA). Herein, we aimed to analyse the possible protective effects of the PPARβ/δ agonist GW0742 on the hyperglycaemic-induced impairment of cAMP-induced relaxation and Kv channel function in rat CA. As compared with low glucose (LG), incubation under high glucose (HG) conditions attenuated the relaxation induced by the adenylate cyclase activator forskolin in CA and this was prevented by GW0742. The protective effect of GW0742 was supressed by a PPARβ/δ antagonist. In myocytes isolated from CA under LG, forskolin enhanced Kv currents and induced hyperpolarization. In contrast, when CA were incubated with HG, Kv currents were diminished and the electrophysiological effects of forskolin were abolished. These deleterious effects were prevented by GW0742. The protective effects of GW0742 on forskolin-induced relaxation and Kv channel function were confirmed in CA from type-1 diabetic rats. In addition, the differences in the relaxation induced by forskolin in CA incubated under LG, HG or HG + GW0742 were abolished by the Kv7 channel inhibitor XE991. Accordingly, GW0742 prevented the down-regulation of Kv7 channels induced by HG. Finally, the preventive effect of GW0742 on oxidative stress and cAMP-induced relaxation were overcome by the pyruvate dehydrogenase kinase 4 (PDK4) inhibitor dichloroacetate (DCA). Our results reveal that the PPARβ/δ agonist GW0742 prevents the impairment of the cAMP-mediated relaxation in CA under HG. This protective effect was associated with induction of PDK4, attenuation of oxidative stress and preservation of Kv7 channel functionItem Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction(Thorax, 2017) Pandolfi, Rachele; Barreira, Bianca; Moreno, Enrique; Lara Acedo, Victor; Morales Cano, Daniel; Martínez Ramas, Andrea; Olaiz Navarro, Beatriz de; Herrero, Raquel; Lorente, Jose Angel; Cogolludo Torralba, Ángel Luis; Perez-Vizcaino, Francisco; Moreno Gutiérrez, LauraBackground Pulmonary hypertension (PH) is frequently observed in patients with acute respiratory distress syndrome (ARDS) and it is associated with an increased risk of mortality. Both acid sphingomyelinase (aSMase) activity and interleukin 6 (IL-6) levels are increased in patients with sepsis and correlate with worst outcomes, but their role in pulmonary vascular dysfunction pathogenesis has not yet been elucidated. Therefore, the aim of this study was to determine the potential contribution of aSMase and IL-6 in the pulmonary vascular dysfunction induced by lipopolysaccharide (LPS). Methods Rat or human pulmonary arteries (PAs) or their cultured smooth muscle cells (SMCs) were exposed to LPS, SMase or IL-6 in the absence or presence of a range of pharmacological inhibitors. The effects of aSMase inhibition in vivo with D609 on pulmonary arterial pressure and inflammation were assessed following intratracheal administration of LPS. Results LPS increased ceramide and IL-6 production in rat pulmonary artery smooth muscle cells (PASMCs) and inhibited pulmonary vasoconstriction induced by phenylephrine or hypoxia (HPV), induced endothelial dysfunction and potentiated the contractile responses to serotonin. Exogenous SMase and IL-6 mimicked the effects of LPS on endothelial dysfunction, HPV failure and hyperresponsiveness to serotonin in PA; whereas blockade of aSMase or IL-6 prevented LPS-induced effects. Finally, administration of the aSMase inhibitor D609 limited the development of endotoxin-induced PH and ventilation-perfusion mismatch. The protective effects of D609 were validated in isolated human PAs. Conclusions Our data indicate that aSMase and IL-6 are not simply biomarkers of poor outcomes but pathogenic mediators of pulmonary vascular dysfunction in ARDS secondary to Gram-negative infections.Item Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension(Antioxidants, 2021) Morales Cano, Daniel; Barreira, Bianca; De Olaiz Navarro, Beatriz; Callejo Arranz, María; Mondejar Parreño, Gema; Esquivel Ruiz, Sergio Antonio; Lorente, José Ángel; Moreno Gutiérrez, Laura; Barberá, Joan Albert; Cogolludo Torralba, Ángel Luis; Pérez Vizcaíno, FranciscoCurrent approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.