Reduced L-carnitine transport in aortic endothelial cells from spontaneously hypertensive rats

Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endothelial dysfunction in hypertension could result from lower L-carnitine transport in this cell type. L-Carnitine transport is mainly mediated by novel organic cation transporters 1 (Octn1, Na+-independent) and 2 (Octn2, Na+-dependent); however, their kinetic properties and potential consequences in hypertension are unknown. We hypothesize that L-carnitine transport kinetic properties will be altered in aortic endothelium from spontaneously hypertensive rats (SHR). L-Carnitine transport was measured at different extracellular pH (pHo 5.5–8.5) in the absence or presence of sodium in rat aortic endothelial cells (RAECs) from non-hypertensive Wistar-Kyoto (WKY) rats and SHR. Octn1 and Octn2 mRNA relative expression was also determined. Dilation of endothelium-intact or denuded aortic rings in response to calcitonine gene related peptide (CGRP, 0.1–100 nmol/L) was measured (myography) in the absence or presence of L-carnitine. Total L-carnitine transport was lower in cells from SHR compared with WKY rats, an effect due to reduced Na+-dependent (Na+dep) compared with Na+-independent (Na+indep) transport components. Saturable L-carnitine transport kinetics show maximal velocity (Vmax), without changes in apparent Km for Na+indep transport in SHR compared with WKY rats. Total and Na+dep component of transport were increased, but Na+indep transport was reduced by extracellular alkalization in WKY rats. However, alkalization reduced total and Na+indep transport in cells from SHR. Octn2 mRNA was higher than Octn-1 mRNA expression in cells from both conditions. Dilation of artery rings in response to CGRP was reduced in vessels from SHR compared with WKY rats. CGRP effect was endothelium-dependent and restored by L-carnitine. All together these results suggest that reduced L-carnitine transport (likely via Na+-dependent Octn2) could limit this compound's potential beneficial effects in RAECs from SHR

Marco activo de recursos de innovación docente: Madrid

Una guía de espacios e instituciones para actividades educativas complementarias en enseñanza secundaria y Formación Profesional

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Efecto Cardioprotector de la L-Carnitina en ratas tratadas con Sunitinib

Ya que el sunitinib no solo es uno de los fármacos más importantes para el tratamiento del carcinoma de células renales y tumores del estroma gastrointestinal resistentes a imatinib, sino que además está siendo evaluado actualmente para una amplia variedad de tumores sólidos -incluyendo cánceres de mama, pulmón y colorrectales-, resulta de gran trascendencia encontrar un medio de impedir o palia r sus efectos adversos, especialmente a nivel cardiovascular. Por ello, y en función de los antecedentes beneficiosos derivados de la suplementación con L-carnitina en diversas patologías que afectan, entre otros, al sistema cardiovascular, nuestra hipótesis de trabajo es que el tratamiento con L-carnitina podría actuar aminorando o evitando la cardiotoxicidad del sunitinib. 2.1. Objetivo general Nuestro objetivo general es demostrar que el tratamiento añadido con L-carnitina mejora ciertos efectos adversos generales, las cifras de presión arterial y los parámetros de estrés oxidativo, inflamación y fibrosis, en ratas tratadas con sunitinib. 2.2. Objetivos específicos 1) Estudiar los efectos del sunitinib sobre el peso corporal y sobre el peso/índice cardiacos en ratas sometidas a un tratamiento crónico con este fármaco, y discutir las modificaciones producidas, en su caso, al añadir L-carnitina de manera simultánea al tratamiento con sunitinib. 2) Evaluar las modificaciones de las cifras de presión arterial sistólica y diastólica, y de la frecuencia cardiaca, en ratas tratadas con sunitinib, así como los efectos de la inclusión de L-carnitina sobre dichas variables. 3) Examinar la capacidad antioxidante a nivel sistémico, determinando diferentes enzimas implicadas en la defensa antioxidante del organismo (GPx, GR y SOD), en ratas tratadas con sunitinib y las modificaciones producidas con el tratamiento combinado de sunitinib más Lcarnitina. 4) Evaluar el estado oxidativo a nivel cardiaco analizando: i) la actividad de las enzimas mencionadas en el punto anterior, así como su expresión génica y proteica, en corazón; ii) los niveles de glutatión reducido (GSH) y glutatión oxidado (GSSG), así como la relación GSH/GSSG en corazón; iii) el grado de peroxidación lipídica y la nitrosilación de proteínas, como marcadores de estrés oxidativo en corazón; iv) los niveles de óxido nítrico y la expresión génica y proteica de la eNOS en corazón; v) la expresión génica de la iNOS en corazón; y vi) la expresión génica y proteica de la subunidad Nox2 de la enzima NADPH oxidasa en corazón. En todos los casos, se compararán los resultados obtenidos en ratas tratadas con sunitinib con los procedentes de ratas tratadas con sunitinib más L-carnitina. 5) Evaluar el proceso de inflamación a nivel cardiaco, determinando la expresión génica de diversas moléculas de relevancia en los procesos inflamatorios (IL-1β, IL-6 e IL-10) en ratas tratadas con sunitinib, y analizar las modificaciones producidas, en su caso, con el tratamiento combinado de sunitinib más L-carnitina. 6) Examinar el grado de fibrosis a nivel cardiaco por medio de: i) estudio histológico del tejido cardiaco, empleando tinciones adecuadas para visualizar las fibras de colágeno y cuantificar el grado de fibrosis; ii) cuantificación de la expresión génica de las fibras de colágeno en los tejidos cardiacos; y iii) cuantificación de la expresión génica de los factores profibróticos TGF-β1 y CTGF en corazón. Los resultados procedentes de ratas tratadas con sunitinib se procesarán en comparación con los obtenidos en ratas tratadas con sunitinib más L-carnitina. 7) Estudiar la posible implicación de la endotelina-1 (ET-1) y de los factores de transcripción NF-κB y PPAR-γ en los mecanismos de acción de la L-carnitina frente a la cardiotoxicidad inducida por sunitinib

Expression of Octn1 and Octn2.

<p>The relative mRNA expression level of Octn1 and Octn2 in RAECs cultures from WKY rats or SHR was estimated from the 2^−ΔΔCT method using the Light Cycler® 480 SW 1.5 relative quantification (delta-delta-Ct) study software as described in Methods. Gene expression levels were normalized to GAPDH mRNA level. *<i>P</i><0.05 versus corresponding values for Octn2. †<i>P</i><0.02 versus corresponding values in SHR. Values are mean ± SEM (n = 15).</p

Transport of L-carnitine in RAECs.

<p>Total, Na⁺-dependent (Na⁺<i>_dep</i>) and Na⁺-independent (Na⁺<i>_indep</i>) L-carnitine transport (20 µmol/L, 3 µCi/mL L-[³H]carnitine, 30 seconds, 37°C) in RAECs from WKY rats or SHR. Transport was assayed in RAECs in passage 3 (P3) (a) and compared with cells in passages 0 (P0) (b), 1 (P1) (c) or 2 (P2) (d). *<i>P</i><0.05 versus all other values, †<i>P</i><0.05 versus corresponding Na⁺<i>_dep</i> values in SHR, ‡<i>P</i><0.05 versus all other values in SHR. Values are mean ± SEM (n = 7–20).</p

Total transport of L-carnitine kinetics.

<p>Total transport of L-carnitine (<i>Total</i>), and the Na⁺-dependent (Na⁺<i>_dep</i>) and Na⁺-independent (Na⁺<i>_indep</i>) transport components (0–80 µmol/L L-carnitine, 3 µCi/mL L-[³H]carnitine, 30 seconds, 37°C) in RAECs cultures from WKY rats (a) or SHR (b). The Eadie-Hofstee plots for transport data in shown for WKY rats (c) and SHR (d) from data in (a) and (b), respectively. Values are mean ± SEM (n = 15).</p

Effect of extracellular pH on saturable transport of L-carnitine, and rat aorta reactivity.

<p>Total saturable transport of L-carnitine (<i>Total</i>), and the Na⁺-dependent (Na⁺<i>_dep</i>) and Na⁺-independent (Na⁺<i>_indep</i>) transport components (20 µmol/L L-carnitine, 3 µCi/mL L-[³H]carnitine, 30 seconds, 37°C) in RAECs cultures from WKY rats (a) or SHR (b) exposed to culture medium with the pH adjusted to different values. (c) Relaxation of 32.5 mmol/L KCl preconstricted endothelium-intact aortic vessel rings (With endothelium) from WKY rats or SHR in response to increasing concentrations of calcitonine gene related peptide (CGRP, 5 minutes), in the absence (-Car) or presence (+Car) of 20 µmol/L L-carnitine (30 minutes). (d) Relaxation of endothelium-denuded aortic vessel rings (Without endothelium) to CGRP as in (c). *<i>P</i><0.05 versus all other values for the corresponding components. Values are mean ± SEM (n = 4–10).</p

Half-maximal effect of extracelular pH on saturable transport of L-carnitine in RAECs.

<p>Total transport of L-carnitine, and the Na⁺-dependent (Na⁺<i>_dep</i>) and Na⁺-independent (Na⁺<i>_indep</i>) transport components (20 µmol/L L-carnitine, 3 µCi/mL L-[³H]carnitine, 30 seconds, 37°C) in RAECs cultures from WKY rats or SHR exposed to culture medium with the pH adjusted to different values (extracellular pH (pH_o) 5.5–8.5) as described in Methods. The stimulatory (<i>SE</i>₅₀) or inhibitory (<i>IE</i>₅₀) effect of pH_o on transport was calculated. <i>ni</i>, not inhibited; <i>ns</i>, not stimulated. *<i>P</i><0.05 versus Total in WKY rats. Values are mean ± SEM (n = 12).</p