Estudio proteómico diferencial en tejido adiposo epicárdico y subcutáneo de pacientes con cardiopatía isquémica

La cardiopatía isquémica es la enfermedad que causa mayor número de muertes e incapacidad en los países desarrollados. El incremento del tejido adiposo en la obesidad, en particular el componente visceral, constituye un importante factor de riesgo cardiovascular. El tejido adiposo epicárdico (TAE) se distribuye de forma preferente siguiendo la adventicia de las arterias coronarias, pudiendo ejercer un efecto paracrino sobre las mismas y/o el miocardio subyacente. Debido a las diferencias que existen entre los tejidos adiposos según su ubicación y a la interacción entre el tejido adiposo con otros tejidos (ya sea de manera paracrina o endocrina), se han planteado los siguientes objetivos: o Analizar las diferencias de expresión proteica existentes entre TAE y tejido adiposo subcutáneo (TAS) de pacientes sometidos a cirugía cardíaca. o Comparar la secreción del tejido adiposo dependiendo de su localización. o Determinar los niveles de expresión y secreción proteica en pacientes afectados por cardiopatía isquémica frente a pacientes sin coronariopatía. En el desarrollo de esta tesis, se ha demostrado que el TAE presenta mayor estrés oxidativo que el TAS en pacientes sometidos a cirugía cardíaca. La expresión de enzimas anti-oxidantes que presentan diferencias en cuanto a su cantidad o a modificaciones postraduccionales (CATA, GSTP1, PDIA1 y PGAM1) sugiere una posible relación de ellos con el mayor estrés oxidativo encontrado en este tejido. Gracias a la separación de los componentes celulares del tejido adiposo, se ha podido evidenciar que los cambios en la producción de radicales libres entre los dos tejidos provienen de la fracción adipocitaria. Las diferencias entre estos dos tejidos no se limitaban sólo a esta observación, sino que también se han encontrado cambios a nivel de la secreción. Así, el TAE es más activo, en términos de secreción proteica, que el TAS. En este aspecto, el TAE secreta al medio de cultivo mayor cantidad de moléculas de transporte lipídico (APOA1 y RBP4) y anti-oxidantes (GSTP1) con respecto al TAS. En el contexto de la cardiopatía isquémica, se ha observado que los pacientes con esta patología tienen aumentadas las diferencias de expresión de los enzimas anti-oxidantes GSTP1, PDIA1 y PGAM1 entre los dos tejidos. Además, también presentan diferencias a nivel de expresión en el TAE de FABP4 y RBP4, sugiriendo modificaciones en el transporte lipídico. Sin embargo, el dato más relevante en este contexto se refleja en la menor secreción de APOA1 por parte del TAE en pacientes con cardiopatía isquémica frente a pacientes sin coronariopatía, dada la importancia de esta molécula como predictor del riesgo cardiovascular. Los cambios observados en el TAE, con respecto al TAS, y su proximidad a las arterias coronarias y al miocardio subyacente sugieren que este tejido pueda estar jugando un papel en la aparición o la progresión de la cardiopatía isquémica

Estudios del secretoma y proteoma de grasa epicárdica han determinado niveles de proteínas implicadas en el transporte de lípidos más bajos en pacientes con cardiopatía isquémica

Comunicaciones a congreso

Receptor for advanced glycation end-products expression in subcutaneous adipose tissue is related to coronary artery disease

OBJECTIVE: Obesity, a risk factor for coronary artery disease (CAD), is associated with inflammation and reactive oxygen species (ROS) production, while advanced glycation end-products, through their receptor (AGER or RAGE), play an important role on these processes. The aim of this study was to analyze the expression levels of RAGE, NADPH oxidase subunits, and catalase in adipose tissue in relation with CAD. DESIGN AND METHODS: Patients undergoing heart surgery were included in two groups: with and without CAD. Epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) biopsies were analyzed for gene expression by RT-quantitative PCR, immunohistochemistry, or western blot. RESULTS: RAGE mRNA and protein expression in SAT from patients with CAD was lower than in patients without CAD. However, there was no change in EAT from patients with or without CAD. P22-PHOX and RAGE gene expression were higher in EAT than in SAT, whereas catalase mRNA levels were lower. NADPH oxidase subunits and catalase mRNA expression were not influenced by CAD. Whereas NADPH oxidase-dependent oxidative response of SAT and EAT to lipid circulating levels could be different; glycemic levels were not related with the analyzed genes expression. CONCLUSIONS: This study demonstrates that RAGE expression in SAT, but not in EAT, is down-regulated in patients with CAD with respect to those without CAD. Although changes were not observed for NADPH oxidase subunits or catalase expression between CAD and non-CAD patients, a possible relationship between ROS production and RAGE expression in adipose tissues cannot be ruled out

Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease

Parkinson’s disease (PD) is a complex and heterogeneous disorder involving multiple genetic and environmental influences. Although a wide range of PD risk factors and clinical markers for the symptomatic motor stage of the disease have been identified, there are still no reliable biomarkers available for the early pre-motor phase of PD and for predicting disease progression. High-throughput RNA-based biomarker profiling and modeling may provide a means to exploit the joint information content from a multitude of markers to derive diagnostic and prognostic signatures. In the field of PD biomarker research, currently, no clinically validated RNA-based biomarker models are available, but previous studies reported several significantly disease-associated changes in RNA abundances and activities in multiple human tissues and body fluids. Here, we review the current knowledge of the regulation and function of non-coding RNAs in PD, focusing on microRNAs, long non-coding RNAs, and circular RNAs. Since there is growing evidence for functional interactions between the heart and the brain, we discuss the benefits of studying the role of non-coding RNAs in organ interactions when deciphering the complex regulatory networks involved in PD progression. We finally review important concepts of harmonization and curation of high throughput datasets, and we discuss the potential of systems biomedicine to derive and evaluate RNA biomarker signatures from high-throughput expression data

The circular RNA MICRA for risk stratification after myocardial infarction

Background: A significant proportion of patients develop heart failure (HF) after acute myocardial infarction (MI). Predicting this development with novel biomarkers would allow tailoring healthcare to each individual. We recently identified a circular RNA called MICRA which was associated with HF development after MI. Here, we tested whether MICRA was able to risk stratify MI patients. Methods: MICRA was assessed in whole blood samples collected at reperfusion in 472 patients with acute MI. Left ventricular ejection fraction (EF) was evaluated by echocardiography at 4 months. Multivariable analyses with ordinal regression were conducted to determine the ability of MICRA to classify patients into 3 EF groups: reduced EF (≤40%), mid-range EF (4149%) and preserved EF (≥50%). Results: Eighty seven patients (18%) had a reduced EF, 106 (22%) had a mid-range EF and 279 (59%) had a preserved EF at 4 months. MICRA classified patients into EF groups with an adjusted odds ratio [95% confidence interval] of 0.78 [0.64–0.95]. MICRA improved the predictive value of a multivariable clinical model as attested by a decrease of the Akaike Information Criteria (p = 0.012). Bootstrap internal validation confirmed the incremental prognostic value of MICRA. Conclusion: We report that the circRNA MICRA improves risk classification after MI, supporting the added value of this novel biomarker in future prognostication strategies

Noncoding RNAs in acute kidney injury

Acute kidney injury (AKI) is an important health issue concerning ∼50% of patients treated in intensive care units. AKI mainly occurs after sepsis, acute ischemia, nephrotoxicity, or hypoxia and leads to severe damage of the kidney and to an increased risk of mortality. The diagnosis of AKI is currently based on creatinine urea levels and diuresis. Yet, novel markers may improve the accuracy of this diagnosis at an early stage of the disease, thereby allowing early prevention and therapy, ultimately leading to a reduction in the need for renal replacement therapy and decreased mortality. Non-protein-coding RNAs or noncoding RNAs are central players in development and disease. They are important regulatory molecules that allow a fine-tuning of gene expression and protein synthesis. This regulation is necessary to maintain homeostasis, and its dysregulation is often associated with disease development. Noncoding RNAs are present in the kidney and in body fluids and their expression is modulated during AKI. This review article assembles the current knowledge of the role of noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, in the pathogenesis of AKI. Their potential as biomarkers and therapeutic targets as well as the challenges to translate research findings to clinical application are discussed. Although microRNAs have entered clinical testing, preclinical and clinical trials are needed before long noncoding RNAs and circular RNAs may be considered as useful biomarkers or therapeutic targets of AKI

Circular RNAs in the cardiovascular system

Until recently considered as rare, circular RNAs (circRNAs) are emerging as important regulators of gene expression. They are ubiquitously expressed and represent a novel branch of the family of non-coding RNAs. Recent investigations showed that circRNAs are regulated in the cardiovascular system and participate in its physiological and pathological development. In this review article, we will provide an overview of the role of circRNAs in cardiovascular health and disease. After a description of the biogenesis of circRNAs, we will summarize what is known of the expression, regulation and function of circRNAs in the cardiovascular system. We will then address some technical aspects of circRNAs research, discussing how artificial intelligence may aid in circRNAs research. Finally, the potential of circRNAs as biomarkers of cardiovascular disease will be addressed and directions for future research will be proposed. Keywords: Non-coding RNAs, Circular RNAs, Cardiovascular system, Cardiovascular disease, Artificial intelligence, Biomarke