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
17 results
Search Results
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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.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.- Project number: 273
Item Elaboración de casos clínicos para el aprendizaje basado en casos prácticos: una herramienta pedagógica para la inmersión en la materia de profesores noveles y un recurso didáctico en la metodología de aprendizaje con participación del estudiante(2023) Gutiérrez López, María Dolores; Caballero Collado, Ricardo; Caso, Javier; Delpón Mosquera, María Eva; García Bueno, Borja; Leza Cerro, Juan Carlos; Lizasoain, Ignacio; McDowell Mata, Karina; Morales, Daniel; Moreno Gutiérrez, Laura; Muñoz Madrigal, Jose Luis; O’Shea Gaya, María Esther; Pérez Vizcaíno, Francisco; Tejerina Maria, Teresa; Vidal Casado, Rebeca; Vidal, Alfonso; Martín Hernández, David; Malan-Müller, Stefanie; Olivencia, Miguel Ángel; Morales, Nuria; Núñez de la Calle, Carlos; Vicente Crespo, Maria Elena; Cogolludo Torralba, Ángel LuisEl proyecto propone la elaboración de nuevos casos clínicos que asemejen situaciones reales sobre los que los estudiantes puedan desarrollar un aprendizaje autónomo dirigido por el profesorado en función de los conceptos que sean de interés para cada grupo farmacológico y acercándole a la situación más cercana a su práctica profesional. Los objetivos del proyecto son: 1) Generar una base de nuevos casos clínicos dirigidos a que los estudiantes trabajen sobre grupos de fármacos en un contexto lo más real posible. Los diferentes casos que se elaboren en este proyecto podrán ser utilizados en la docencia de diversas asignaturas impartidas por miembros del departamento de Farmacología y Toxicología. Las sesiones dirigidas al estudio basado en la resolución de casos se plantean como una herramienta docente que tiene como finalidad el desarrollo de competencias transversales como promover la motivación, el trabajo en equipo, la participación de los estudiantes en los debates, así como, fomentar el pensamiento crítico y el conocimiento del método científico. Este tipo de aprendizaje en contexto facilita la integración de los conocimientos y su mayor retención además de la dotar a los estudiantes con las habilidades para fomentar un aprendizaje continuo. 2) Apoyar la formación del profesorado de reciente incorporación, así como del personal investigador que participan como colabores en tareas docentes del departamento y que podrían ser potenciales futuros docentes. Item Ceramide and Regulation of Vascular Tone(International Journal of Molecular Sciences, 2019) Cogolludo Torralba, Ángel Luis; Villamor, Eduardo; Pérez Vizcaíno, Francisco; Moreno Gutiérrez, LauraIn addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases.Item Effects of Quercetin in a Rat Model of Hemorrhagic Traumatic Shock and Reperfusion(Molecules, 2016) Chamorro, Virginia; Pandolfi, Rachele; Moreno Gutiérrez, Laura; Barreira, Bianca; Martínez-Ramas, Andrea; Morales Cano, Daniel; Ruiz-Cabello, Jesús; Lorente, José; Duarte, Juan; Cogolludo Torralba, Ángel Luis; Álvarez-Sala Walther, Jose Luis; Pérez Vizcaíno, FranciscoBackground: We hypothesized that treatment with quercetin could result in improved hemodynamics, lung inflammatory parameters and mortality in a rat model of hemorrhagic shock. Methods: Rats were anesthetized (80 mg/kg ketamine plus 8 mg/kg xylazine i.p.). The protocol included laparotomy for 15 min (trauma), hemorrhagic shock (blood withdrawal to reduce the mean arterial pressure to 35 mmHg) for 75 min and resuscitation by re-infusion of all the shed blood plus lactate Ringer for 90 min. Intravenous quercetin (50 mg/kg) or vehicle were administered during resuscitation. Results: There was a trend for increased survival 84.6% (11/13) in the treated group vs. the shock group 68.4% (13/19, p > 0.05 Kaplan–Meier). Quercetin fully prevented the development of lung edema. The activity of aSMase was increased in the shock group compared to the sham group and the quercetin prevented this effect. However, other inflammatory markers such as myeloperoxidase activity, interleukin-6 in plasma or bronchoalveolar fluid were similar in the sham and shock groups. We found no bacterial DNA in plasma in these animals. Conclusions: Quercetin partially prevented the changes in blood pressure and lung injury in shock associated to hemorrhage and reperfusion.Item 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 HIV transgene expression impairs K+ channel function in the pulmonary vasculature(American Journal of Physiology - Lung Cellular and Molecular Physiology, 2018) Mondejar Parreño, Gema; Morales Cano, Daniel; Barreira, Bianca; Callejo, Maria; Ruiz-Cabello Osuna, Jesús; Moreno Gutiérrez, Laura; Esquivel Ruiz, Sergio Antonio; Mathie, Alistair; Butrous, Ghazwan; Pérez Vizcaíno, Francisco; Cogolludo Torralba, Ángel LuisHuman immunodeficiency virus (HIV) infection is an established risk factor for pulmonary arterial hypertension (PAH); however, the pathogenesis of HIV-related PAH remains unclear. Since K+ channel dysfunction is a common marker in most forms of PAH, our aim was to analyze whether the expression of HIV proteins is associated with impairment of K+ channel function in the pulmonary vascular bed. HIV transgenic mice (Tg26) expressing seven of the nine HIV viral proteins and wild-type (WT) mice were used. Hemodynamic assessment was performed by echocardiography and catheterization. Vascular reactivity was studied in endothelium-intact pulmonary arteries. K+ currents were recorded in freshly isolated pulmonary artery smooth muscle cells (PASMC) using the patch-clamp technique. Gene expression was assessed using quantitative RT-PCR. PASMC from Tg26 mice had reduced K+ currents and were more depolarized than those from WT. Whereas voltage-gated K+ channel 1.5 (Kv1.5) currents were preserved, pH-sensitive noninactivating background currents (IKN) were nearly abolished in PASMC from Tg26 mice. Tg26 mice had reduced lung expression of Kv7.1 and Kv7.4 channels and decreased responses to the Kv7.1 channel activator L-364,373 assessed by vascular reactivity and patch-clamp experimental approaches. Although we found pulmonary vascular remodeling and endothelial dysfunction in Tg26 mice, this was not accompanied by changes in hemodynamic parameters. In conclusion, the expression of HIV proteins in vivo impairs pH-sensitive IKN and Kv7 currents. This negative impact of HIV proteins in K+ channels was not sufficient to induce PAH, at least in mice, but may play a permissive or accessory role in the pathophysiology of HIV-associated PAH.Item Ceramide Mediates Acute Oxygen Sensing in Vascular Tissues(Antioxidants and Redox Signaling, 2014) Moreno Gutiérrez, Laura; Moral Sanz, Javier; Morales Cano, Daniel; Barreira, Bianca; Moreno, Enrique; Ferrarini, Alessia; Pandolfi, Rachele; Ruperez, Francisco J.; Cortijo, Julio; Sánchez Luna, Manuel Ramón; Villamor, Eduardo; Pérez Vizcaíno, Francisco; Cogolludo Torralba, Ángel LuisAims: A variety of vessels, such as resistance pulmonary arteries (PA) and fetoplacental arteries and the ductus arteriosus (DA) are specialized in sensing and responding to changes in oxygen tension. Despite opposite stimuli, normoxic DA contraction and hypoxic fetoplacental and PA vasoconstriction share some mechanistic features. Activation of neutral sphingomyelinase (nSMase) and subsequent ceramide production has been involved in hypoxic pulmonary vasoconstriction (HPV). Herein we aimed to study the possible role of nSMase-derived ceramide as a common factor in the acute oxygen-sensing function of specialized vascular tissues. Results: The nSMase inhibitor GW4869 and an anticeramide antibody reduced the hypoxic vasoconstriction in chicken PA and chorioallantoic arteries (CA) and the normoxic contraction of chicken DA. Incubation with interference RNA targeted to SMPD3 also inhibited HPV. Moreover, ceramide and reactive oxygen species production were increased by hypoxia in PA and by normoxia in DA. Either bacterial sphingomyelinase or ceramide mimicked the contractile responses of hypoxia in PA and CA and those of normoxia in the DA. Furthermore, ceramide inhibited voltage-gated potassium currents present in smooth muscle cells from PA and DA. Finally, the role of nSMase in acute oxygen sensing was also observed in human PA and DA. Innovation: These data provide evidence for the proposal that nSMase-derived ceramide is a critical player in acute oxygen-sensing in specialized vascular tissues. Conclusion: Our results indicate that an increase in ceramide generation is involved in the vasoconstrictor responses induced by two opposite stimuli, such as hypoxia (in PA and CA) and normoxia (in DA).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 resuscitation