Person: Pérez Vizcaíno, Francisco
Loading...
First Name
Francisco
Last Name
Pérez Vizcaíno
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
16 results
Search Results
Now showing 1 - 10 of 16
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 Serum MicroRNAs as Biomarkers of Sepsis and Resuscitation(Applied Sciences, 2021) Oteiza, Lorena; Ferruelo, Antonio; Nín, Nicolás; Arenillas Baquero, Mario; Paula, Marta de; Pandolfi, Rachele; Moreno Gutiérrez, Laura; Herrero, Raquel; González Rodríguez, Paloma; Peñuelas, Óscar; Pérez Vizcaíno, Francisco; Lorente, José ÁngelThere is a lack of biomarkers of sepsis and the resuscitation status. Our objective was to prove that the serum expression of certain microribonucleic acids (miRNAs) is differentially regulated in sepsis and is sensitive to different resuscitation regimes. Anesthetized pigs (Sus scrofa domesticus) received no treatment (n = 15) or intravenous live E. coli (n = 24). The septic animals received 0.9% saline at 4 mL/kg/h (n = 8) (low resuscitation group (LoR)) or 10–17 mL/kg/h (high resuscitation group (HiR)) (n = 8 each group). Blood samples were obtained at the end of the experiment for measurement of seven different miRNAs (RT-qPCR, Qiagen, Hilden, Germany). The serum expression of miR-146a-5p and miR-34a-5p increased significantly in the septic group, and miR-146a-5p was significantly lower in the HiR group than in the LoR group. The toll-like receptor signaling pathway involving 22 target proteins was significantly (adjusted p = 3.87 × 10−4) regulated by these two microRNAs (KEGG). Highly significant (p value = 2.22 × 10−16) protein–protein interactions (STRING) were revealed for these 22 hits. MiR-146a-5p and miR-34a-5p were identified as biomarkers of sepsis, and miRNA146a-5p seemed to be a biomarker of the intensity of the resuscitationItem Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency(Biomolecules, 2021) Callejo Arranz, María; Morales Cano, Daniel; Mondejar Parreño, Gema; Barreira, Bianca; Esquivel Ruiz, Sergio Antonio; Olivencia Plaza, Miguel Ángel; Moreno Gutiérrez, Laura; Cogolludo Torralba, Ángel Luis; Pérez Vizcaíno, FranciscoVitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.Item Impact of Nutrition on Pulmonary Arterial Hypertension(Nutrients, 2020) Callejo Arranz, María; Barberá, Joan Albert; Duarte, Juan; Pérez Vizcaíno, FranciscoPulmonary arterial hypertension (PAH) is characterized by sustained vasoconstriction, vascular remodeling, inflammation, and in situ thrombosis. Although there have been important advances in the knowledge of the pathophysiology of PAH, it remains a debilitating, limiting, and rapidly progressive disease. Vitamin D and iron deficiency are worldwide health problems of pandemic proportions. Notably, these nutritional alterations are largely more prevalent in PAH patients than in the general population and there are several pieces of evidence suggesting that they may trigger or aggravate disease progression. There are also several case reports associating scurvy, due to severe vitamin C deficiency, with PAH. Flavonoids such as quercetin, isoflavonoids such as genistein, and other dietary polyphenols including resveratrol slow the progression of the disease in animal models of PAH. Finally, the role of the gut microbiota and its interplay with the diet, host immune system, and energy metabolism is emerging in multiple cardiovascular diseases. The alteration of the gut microbiota has also been reported in animal models of PAH. It is thus possible that in the near future interventions targeting the nutritional status and the gut dysbiosis will improve the outcome of these patients.Item Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice(British Journal of Pharmacology, 2023) Olivencia Plaza, Miguel Ángel; Gil De Biedma Elduayen, Leticia; Giménez Gómez, Pablo; Bianca Barreira; Argentina Fernández; Javier Angulo; Colado Megías, María Isabel; O'Shea Gaya, María Esther; Pérez Vizcaíno, FranciscoBackground and purposeAlcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED.Experimental approachED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively.Key resultsIn CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre‐treatment with tempol prevented alcohol‐induced erectile dysfunction.Conclusions and implicationsOur results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.Item Supplementation with a Cocoa–Carob Blend, Alone or in Combination with Metformin, Attenuates Diabetic Cardiomyopathy, Cardiac Oxidative Stress and Inflammation in Zucker Diabetic Rats(Antioxidants, 2022) García Díez, Esther; López-Oliva Muñoz, María Elvira; Caro Vadillo, Alicia; Pérez Vizcaíno, Francisco; Pérez Jiménez, Jara; Ramos, Sonia; Martín, María ÁngelesDiabetic cardiomyopathy (DCM) is one of the main causes of mortality among diabetic patients, with oxidative stress and inflammation major contributors to its development. Dietary flavonoids show strong antioxidant and anti-inflammatory activities, although their potential additive outcomes in combination with antidiabetic drugs have been scarcely explored. The present study investigates the cardioprotective effects of a cocoa–carob blend (CCB) diet, rich in flavonoids, alone or in combination with metformin, in the development of DCM. Zucker diabetic fatty rats (ZDF) were fed with a CCB rich-diet or a control diet, with or without metformin for 12 weeks. Glucose homeostasis, cardiac structure and function, and oxidative and inflammatory biomarkers were analysed. CCB improved glucose homeostasis, and mitigated cardiac dysfunction, hypertrophy, and fibrosis in ZDF rats. Mechanistically, CCB counteracted oxidative stress in diabetic hearts by down-regulating NADPH oxidases, reducing reactive oxygen species (ROS) generation and modulating the sirtuin-1 (SIRT1)/ nuclear factor E2-related factor 2 (Nrf2) signalling pathway, overall improving antioxidant defence. Moreover, CCB suppressed inflammatory and fibrotic reactions by inhibiting nuclear factor kappa B (NFκB) and pro-inflammatory and pro-fibrotic cytokines. Noteworthy, several of these effects were further improved in combination with metformin. Our results demonstrate that CCB strongly prevents the cardiac remodelling and dysfunction observed in diabetic animals, highlighting its potential, alone or in adjuvant therapy, for treating DCM.Item Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension.(Antioxidants, 2021) Morales Cano, Daniel; Barreira Barba, Bianca; Olaiz Navarro, Beatriz De; 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.Item Supplemental Figure 1. Protein expression of survivin, eNOS and phospho-eNOS and beta-actin in rats with pulmonary hypertension.(2020) Calleja, María; Mondejar Parreño, Gema; Pérez Vizcaíno, FranciscoSupplemental Figure 1. Original Western blots showing the protein expression of survivin, eNOS and phospho-eNOS and the housekeeping gene beta-actin in rats treated with a standard (+) or a vitD deficient diet (-) for 5 weeks and with normoxia (nmx) or hypoxia (10% O2) and sugen (SuHx) for two additional weeks.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 Total, Bioavailable, and Free Vitamin D Levels and Their Prognostic Value in Pulmonary Arterial Hypertension(Journal of Clinical Medicine, 2020) Callejo Arranz, María; Mondejar Parreño, Gema; Esquivel Ruiz, Sergio Antonio; Olivencia Plaza, Miguel Ángel; Moreno Gutiérrez, Laura; Blanco, Isabel; Escribano Subías, María Pilar; Cogolludo Torralba, Ángel Luis; Barbera, Joan Albert; Pérez Vizcaíno, FranciscoIntroduction: Epidemiological studies suggest a relationship between vitamin D deficiency and cardiovascular and respiratory diseases. However, whether total, bioavailable, and/or free vitamin D levels have a prognostic role in pulmonary arterial hypertension (PAH) is unknown. We aimed to determine total, bioavailable, and free 25-hydroxy-vitamin D (25(OH)vitD) plasma levels and their prognostic value in PAH patients. Methods: In total, 67 samples of plasma from Spanish patients with idiopathic, heritable, or drug-induced PAH were obtained from the Spanish PH Biobank and compared to a cohort of 100 healthy subjects. Clinical parameters were obtained from the Spanish Registry of PAH (REHAP). Results: Seventy percent of PAH patients had severe vitamin D deficiency (total 25(OH)vitD < 10 ng/mL) and secondary hyperparathyroidism. PAH patients with total 25(OH)vitD plasma above the median of this cohort (7.17 ng/mL) had better functional class and higher 6-min walking distance and TAPSE (tricuspid annular plane systolic excursion). The main outcome measure of survival was significantly increased in these patients (age-adjusted hazard ratio: 5.40 (95% confidence interval: 2.88 to 10.12)). Vitamin D-binding protein (DBP) and albumin plasma levels were downregulated in PAH. Bioavailable 25(OH)vitD was decreased in PAH patients compared to the control cohort. Lower levels of bioavailable 25(OH)vitD (<0.91 ng/mL) were associated with more advanced functional class, lower exercise capacity, and higher risk of mortality. Free 25(OH)vitD did not change in PAH; however, lower free 25(OH)vitD (<1.53 pg/mL) values were also associated with high risk of mortality. Conclusions: Vitamin D deficiency is highly prevalent in PAH, and low levels of total 25(OH)vitD were associated with poor prognosis.