Monocyte Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Expression Correlates with cIMT in Mexican Hypertensive Patients. / Expressão de Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade (LRP1) em Monócito em Correlação com EIMC em Pacientes Mexicanos Hipertensos.

BACKGROUND: Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. OBJECTIVE: In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. METHODS: The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. RESULTS: HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). CONCLUSION: An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65).

FUNDAMENTO: A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. OBJETIVO: Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. MÉTODOS: A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. RESULTADOS: O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). CONCLUSÃO: Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65).

Expressão de Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade (LRP1) em Monócito em Correlação com EIMC em Pacientes Mexicanos Hipertensos / Monocyte Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Expression Correlates with cIMT in Mexican Hypertensive Patients

Resumo Fundamento A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. Objetivo Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. Métodos A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. Resultados O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). Conclusão Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65)

Abstract Background Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. Objective In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. Methods The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. Results HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). Conclusion An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65)

Biomarcadores epigenéticos y enfermedad cardiovascular: los microARN circulantes / Epigenetic biomarkers and cardiovascular disease: circulating microRNAs

Los microARN (miARN) son una clase de ARN no codificante de pequeño tamaño (20-25 nucleótidos) que participan en la regulación génica. En los últimos años, los miARN han emergido como un mecanismo epigenético clave en el desarrollo y en la funcionalidad del sistema cardiovascular. Estas especies moleculares regulan funciones básicas en prácticamente todos los tipos celulares y por ello están directamente asociadas con la fisiopatología de un gran número de enfermedades cardiovasculares. Desde su relativamente reciente descubrimiento en fluidos extracelulares, se ha estudiado los miARN como potenciales biomarcadores de enfermedad. Son numerosos los estudios que proponen a los miARN como biomarcadores circulantes de diferentes patologías cardiovasculares (infarto de miocardio, enfermedad coronaria o insuficiencia cardiaca, entre otras), incluso con propiedades fisicoquímicas y bioquímicas superiores a los indicadores proteicos convencionales utilizados actualmente en la práctica clínica. En el presente trabajo se ofrece una breve introducción al campo de los miARN, con especial atención a su potencial aplicación clínica. Esta incluye su posible papel como nuevos biomarcadores de diagnóstico o de pronóstico en la enfermedad cardiovascular (AU)

MicroRNAs (miRNAs) are a class of small noncoding RNA (20-25 nucleotides) involved in gene regulation. In recent years, miRNAs have emerged as a key epigenetic mechanism in the development and physiology of the cardiovascular system. These molecular species regulate basic functions in virtually all cell types, and are therefore directly associated with the pathophysiology of a large number of cardiovascular diseases. Since their relatively recent discovery in extracellular fluids, miRNAs have been studied as potential biomarkers of disease. A wide array of studies have proposed miRNAs as circulating biomarkers of different cardiovascular pathologies (eg, myocardial infarction, coronary heart disease, and heart failure, among others), which may have superior physicochemical and biochemical properties than the conventional protein indicators currently used in clinical practice. In the present review, we provide a brief introduction to the field of miRNAs, paying special attention to their potential clinical application. This includes their possible role as new diagnostic or prognostic biomarkers in cardiovascular disease (AU)

MicroRNA circulantes como reguladores de la respuesta molecular al ejercicio en personas sanas / Circulating microRNA as regulators of the molecular response in exercise in healthy people

Los microRNAs circulantes (c-miRNAs) son reguladores de la expresión génica y mediadores de la comunicación intercelular, con un gran potencial como coordinadores de la respuesta molecular al ejercicio y, por tanto, con eventuales implicaciones prácticas para la salud y el rendimiento. Sin embargo, su respuesta al ejercicio agudo y al entrenamiento en personas sanas es poco conocida, principalmente porque hasta el momento se ha publicado un número reducido de artículos, con resultados dispares. El objetivo de esta revisión es agrupar y sintetizar el conocimiento disponible, analizar las causas de esta heterogeneidad en los resultados e identificar las principales perspectivas de futuro en esta área. Los resultados de los trabajos incluidos en esta revisión muestran que el ejercicio agudo y el entrenamiento inducen una respuesta en el perfil de c-miRNAs influida por el modelo, duración, intensidad y dosis de ejercicio. Queda pendiente, no obstante, conocer su origen, forma de transporte, destino, así como validar sus dianas génicas. Sin embargo, estos estudios muestran entre sí numerosas diferencias metodológicas (técnica de detección, número y tipo de c-miRNAs analizados, estrategia de normalización), en el diseño experimental (puntos de muestreo) y en las características de los sujetos (edad, historial de entrenamiento), que hace difícil, tanto establecer comparaciones directas entre ellos, como extraer conclusiones generales sólidas. Finalmente, este papel del ejercicio, como modulador del perfil de c-miRNAs, podría constituir una alternativa viable y coadyuvante a las terapias farmacológicas y dietéticas basadas en miRNAs que actualmente se encuentran en desarrollo. Además, su validación como biomarcadores de ejercicio podría contribuir al desarrollo de recomendaciones de ejercicio más precisas, a optimizar su aplicación como herramienta preventiva o terapéutica y a explorar los límites máximos del ejercicio saludable

Circulating microRNAs (c-miRNAs) are cell-to-cell communicators implicated in the regulation of molecular responses with strong potential in exercise and practical implications in health. Despite this fact, the number of papers published on this topic is scarce and with inconsistent results. Thus, the aim of this review was to summarize the information available, to analyze the heterogeneity of the results and to identify which are the future perspectives in this field of research. The results of the studies included in this revision clearly show that acute exercise and training induce a response in c-miRNA profile. This response depends on the model, intensity and dose of exercise. However, there are some questions which must be answered: what are the secretory organs or tissues, the mechanisms of transport, and the tissue and gene targets. A number of differences between studies in the methodologies used (detection technique, number of c-miRNAs analyzed, normalization strategy), in the experimental design (sampling points) and in the characteristics of the participants (aging, exercise background, dietary intake) makes it difficult to establish direct comparisons and to draw firm conclusions. Finally, this role of exercise as c-miRNA profile modulator, could be considered a valuable alternative to upcoming pharmacological and nutritional interventions based on miRNAs. Moreover, the validation of c-miRNAs as biomarkers of exercise will allow the development of more specific recommendations, using training as a therapeutic and preventive tool, and exploring the maximal limits for a safe and healthy exercise

microRNA expression profile in human coronary smooth muscle cell-derived microparticles is a source of biomarkers / El perfil de expresión de microARN en micropartículas secretadas por células musculares lisas de arterias coronarias humanas es una fuente de biomarcadores

Introduction: microRNA (miRNA) expression profile of extracellular vesicles is a potential tool for clinical practice. Despite the key role of vascular smooth muscle cells (VSMC) in cardiovascular pathology, there is limited information about the presence of miRNAs in microparticles secreted by this cell type, including human coronary artery smooth muscle cells (HCASMC). Here, we tested whether HCASMC-derived microparticles contain miRNAs and the value of these miRNAs as biomarkers. Methods: HCASMC and explants from atherosclerotic or non-atherosclerotic areas were obtained from coronary arteries of patients undergoing heart transplant. Plasma samples were collected from: normocholesterolemic controls (N=12) and familial hypercholesterolemia (FH) patients (N=12). Both groups were strictly matched for age, sex and cardiovascular risk factors. Microparticle (0.1-1μm) isolation and characterization was performed using standard techniques. VSMC-enriched miRNAs expression (miR-21-5p, -143-3p, -145-5p, -221-3p and -222-3p) was analyzed using RT-qPCR. Results: Total RNA isolated from HCASMC-derived microparticles contained small RNAs, including VSMC-enriched miRNAs. Exposition of HCASMC to pathophysiological conditions, such as hypercholesterolemia, induced a decrease in the expression level of miR-143-3p and miR-222-3p in microparticles, not in cells. Expression levels of miR-222-3p were lower in circulating microparticles from FH patients compared to normocholesterolemic controls. Microparticles derived from atherosclerotic plaque areas showed a decreased level of miR-143-3p and miR-222-3p compared to non-atherosclerotic areas. Conclusions: We demonstrated for the first time that microparticles secreted by HCASMC contain microRNAs. Hypercholesterolemia alters the microRNA profile of HCASMC-derived microparticles. The miRNA signature of HCASMC-derived microparticles is a source of cardiovascular biomarkers

Introducción: Los datos sobre la presencia de microARN en micropartículas liberadas por células de músculo liso vascular (VSMC) y en particular de las células de músculo liso de arteria coronaria humana (HCASMC) son limitados. Por ello, hemos analizado el contenido de miARN en micropartículas liberadas por HCASMC y su posible potencial como biomarcadores. Métodos: Los explantes de arterias coronarias se obtuvieron de pacientes sometidos a trasplante de corazón. Las muestras de plasma se obtuvieron de 2 grupos de estudio: controles normocolesterolémicos (n=12) y pacientes con hipercolesterolemia familiar (HF) (n=12). El aislamiento de micropartículas (0,1-1μm) se llevó a cabo mediante técnicas estándar. La expresión de los miARN típicos de VSMC (miR-21-5p, -143-3p, -145-5p, -221-3p y -222-3p) se analizó mediante RT-qPCR. Resultados: El ARN total aislado a partir de micropartículas procedentes de HCASMC presentó miARN típicos de VSMC. La exposición de HCASMC a condiciones de hipercolesterolemia indujo la reducción en la expresión de miR-143-3p y de miR-222-3p en las micropartículas. Los niveles de expresión de miR-222-3p en micropartículas circulantes fueron inferiores en pacientes de HF en comparación con controles normocolesterolémicos. Las micropartículas liberadas por áreas de placa aterosclerótica mostraron una disminución de los niveles de miR-143-3p y de miR-222-3p en comparación con las de áreas no ateroscleróticas. Conclusiones: Demostramos la presencia de microARN en micropartículas liberadas por HCASMC. La exposición celular a hipercolesterolemia altera el perfil de microARN de estas micropartículas. El perfil de microARN de micropartículas liberadas por HCASMC es una fuente de biomarcadores