Person: Pérez Vizcaíno, Francisco
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First Name
Francisco
Last Name
Pérez Vizcaíno
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
3 results
Search Results
Now showing 1 - 3 of 3
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 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.