Person:
Cogolludo Torralba, Ángel Luis

First Name

Ángel Luis

Last Name

Cogolludo Torralba

URI

https://hdl.handle.net/20.500.14352/78971

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Farmacología y Toxicología

Area

Farmacología

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Now showing 1 - 10 of 25

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, Francisco
Introduction: 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.
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 Luis
Aims 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
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 Luis
El 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.
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 Luis
Reduced 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.
Ceramide and Regulation of Vascular Tone
(International Journal of Molecular Sciences, 2019) Cogolludo Torralba, Ángel Luis; Villamor, Eduardo; Pérez Vizcaíno, Francisco; Moreno Gutiérrez, Laura
In 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.
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, Francisco
Background: 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.
Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities
(Plos Pathogens, 2023) Kumar, Rahul; Cogolludo Torralba, Ángel Luis; Pérez Vizcaíno, Francisco; Morales Cano, Daniel; Dhillon, Navneet K.; Kenneth Stapleford
The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.
Functional Assembly of Kv7.1/Kv7.5 Channels With Emerging Properties on Vascular Muscle Physiology
(Arteriosclerosis, Thrombosis, and Vascular Biology, 2014) Oliveras, Anna; Roura Ferrer, Meritxell; Solé, Laura; Cruz, Alicia de la; Prieto, Angela; Etxebarria, Ainhoa; Manils, Joan; Morales Cano, Daniel; Condom, Enric; Soler, Concepció; Cogolludo Torralba, Ángel Luis; Valenzuela, Carmen; Villarroel, Alvaro; Comes, Núria; Felipe, Antonio
Objective—Voltage-dependent K+ (Kv) channels from the Kv7 family are expressed in blood vessels and contribute to cardiovascular physiology. Although Kv7 channel blockers trigger muscle contractions, Kv7 activators act as vasorelaxants. Kv7.1 and Kv7.5 are expressed in many vessels. Kv7.1 is under intense investigation because Kv7.1 blockers fail to modulate smooth muscle reactivity. In this study, we analyzed whether Kv7.1 and Kv7.5 may form functional heterotetrameric channels increasing the channel diversity in vascular smooth muscles. Approach and Results—Kv7.1 and Kv7.5 currents elicited in arterial myocytes, oocyte, and mammalian expression systems suggest the formation of heterotetrameric complexes. Kv7.1/Kv7.5 heteromers, exhibiting different pharmacological characteristics, participate in the arterial tone. Kv7.1/Kv7.5 associations were confirmed by coimmunoprecipitation, fluorescence resonance energy transfer, and fluorescence recovery after photobleaching experiments. Kv7.1/Kv7.5 heterotetramers were highly retained at the endoplasmic reticulum. Studies in HEK-293 cells, heart, brain, and smooth and skeletal muscles demonstrated that the predominant presence of Kv7.5 stimulates release of Kv7.1/Kv7.5 oligomers out of lipid raft microdomains. Electrophysiological studies supported that KCNE1 and KCNE3 regulatory subunits further increased the channel diversity. Finally, the analysis of rat isolated myocytes and human blood vessels demonstrated that Kv7.1 and Kv7.5 exhibited a differential expression, which may lead to channel diversity. Conclusions—Kv7.1 and Kv7.5 form heterotetrameric channels increasing the diversity of structures which fine-tune blood vessel reactivity. Because the lipid raft localization of ion channels is crucial for cardiovascular physiology, Kv7.1/Kv7.5 heteromers provide efficient spatial and temporal regulation of smooth muscle function. Our results shed light on the debate about the contribution of Kv7 channels to vasoconstriction and hypertension.
Cirrhosis decreases vasoconstrictor response to electrical field stimulation in rat mesenteric artery: role of calcitonin gene-related peptide
(Experimental Physiology, 2011) Blanco-Rivero, Javier; Márquez-Rodas, Iván; Sastre, Esther; Cogolludo Torralba, Ángel Luis; Pérez Vizcaíno, Francisco; Del Campo Milán, Lara; Nava, Mª Paz; Balfagón, Gloria
Our study determines alterations in the vasoconstrictor response elicited by electric field stimulation (EFS) in mesenteric arteries from cirrhotic rats treated with CCl(4), and how calcitonin gene-related peptide (CGRP) participates in this response. Vasoconstriction induced by EFS was analysed in the absence and presence of the CGRP receptor antagonist CGRP(8-37) in arterial segments from control and cirrhotic rats. The vasodilator response to exogenous CGRP was tested in both groups of rats, and the interference of the guanylate cyclase inhibitor ODQ or the K(ATP) channel blocker glibenclamide was analysed only in segments from cirrhotic rats. The vasodilator response to the K(ATP) channel opener pinacidil and to 8-bromo-cyclic GMP was tested. The K(ATP) currents were recorded using the patch-clamp technique. Expression of receptor activity-modifying protein 1 (RAMP1), calcitonin receptor-like receptor, Kir 6.1 and sulfonylurea receptor 2B (SUR2B) was also analysed. Release of CGRP and cGMP was measured. The EFS-elicited vasoconstriction was less in segments from cirrhotic rats. The presence of CGRP(8-37) increased the EFS-induced response only in segments from cirrhotic rats. The CGRP-induced vasodilatation was greater in segments from cirrhotic rats, and was inhibited by ODQ or glibenclamide. Both pinacidil and 8-bromo-cyclic GMP induced a stronger vasodilator response in segments from cirrhotic rats. Pinacidil induced greater K(ATP) currents in cirrhotic myocytes. Expression of RAMP1, calcitonin receptor-like receptor, Kir 6.1 and SUR2B was not modified by liver cirrhosis. Liver cirrhosis increased CGRP release, but did not modify cGMP formation. The decreased vasoconstrictor response to EFS in cirrhosis is mediated by increased vasodilator response to CGRP, as well as increased K(ATP) channel gating. This effect of CGRP may play a role in the splanchnic vasodilatation present in liver cirrhosis.
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, Francisco
Vitamin 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.