Neus Martínez-Micaelo

Institut d'Investigació Sanitària Pere Virgili

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L. Masana

Institut d'Investigació Sanitària Pere Virgili

Josefa Girona

Institut d'Investigació Sanitària Pere Virgili

Ricardo Rodríguez‐Calvo

Institut d'Investigació Sanitària Pere Virgili

Núria Amigó

Universidad Rovira i Virgili

Mercedes Heras

Hospital Universitari Sant Joan de Reus

Noemi González‐Abuín

Institut d'Investigació Biomédica de Bellvitge

Mayte Blay

Universidad Rovira i Virgili

Montserrat Pinent

Universidad Rovira i Virgili

Anna Ardévol

Universidad Rovira i Virgili

Josep M. Alegret

Hospital Universitari Sant Joan de Reus

Cooperative Institutions

Universidad Rovira i Virgili

Institut d'Investigació Sanitària Pere Virgili

Instituto de Salud Carlos III

Hospital Universitari Sant Joan de Reus

Centro de Investigación Biomédica en Red

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Universitat Autònoma de Barcelona

Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition

Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

Universitat de Barcelona

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Bicuspid Aortic Valve and Endothelial Dysfunction: Current Evidence and Potential Therapeutic Targets

Frontiers in Physiology (2020)

Borja Antequera-González Neus Martínez-Micaelo Josep M. Alegret

Bicuspid aortic valve (BAV), the most frequent congenital heart malformation, is characterized by the presence of a two-leaflet aortic valve instead of a three-leaflet one. BAV disease progression is associated with valvular dysfunction (in the form of stenosis or regurgitation) and aortopathy, which can lead to aneurysm and aortic dissection. This morphological abnormality modifies valve dynamics and promotes eccentric blood flow, which gives rise to alterations of the flow pattern and wall shear stress (WSS) of the ascending aorta. Recently, evidence of endothelial dysfunction (ED) in BAV disease has emerged. Different studies have addressed a reduced endothelial functionality by analyzing various molecular biomarkers and cellular parameters in BAV patients. Some authors have found impaired functionality of circulating endothelial progenitors in these patients, associating it with valvular dysfunction and aortic dilation. Others focused on systemic endothelial function by measuring artery flow-mediated dilation (FMD), showing a reduced FMD in BAV individuals. Novel biomarkers like increased endothelial microparticles (EMP), which are related to ED, have also been discovered in BAV patients. Finally, latest studies indicate that in BAV, endothelial-to-mesenchymal transition (EndoMT) may also be de-regulated, which could be caused by genetic, hemodynamic alterations, or both. Different hypothesis about the pathology of ED in BAV are nowadays being debated. Some authors blamed this impaired functionality just on genetic abnormalities, which could lead to a pathological aorta. Nevertheless, thanks to the development of new and high-resolution imaging techniques like 4D flow MRI, hemodynamics has gained great attention. Based on latest studies, alterations in blood flow seem to cause proper modification of the endothelial cells (ECs) function and morphology. It also seems to be associated with aortic dilation and decreased vasodilators expression, like nitric oxide (NO). Although nowadays ED in BAV has been reported by many, it is not clear which its main cause may be. Comprehending the pathways that promote ED and its relevance in BAV could help further understand and maybe prevent the serious consequences of this disease. This review will discuss the ED present in BAV, focusing on the latest evidence, biomarkers for ED and potential therapeutic targets (Figure 1).

Endothelial Dysfunction

Bicuspid valve

10.3389/fphys.2020.01015

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Citations (23)

Plasma glucose, triglycerides, VLDL, leptin and resistin levels as potential biomarkers for myocardial fat in mice

Clínica e Investigación en Arteriosclerosis (English Edition) (2020)

Ricardo Rodríguez‐Calvo Sara Samino Sandra Guaita‐Esteruelas Neus Martínez-Micaelo Mercedes Heras

Resistin

10.1016/j.artere.2019.05.003

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Citations (7)

Grape-Seed Procyanidins Prevent the Cafeteria-Diet-Induced Decrease of Glucagon-Like Peptide-1 Production

Journal of Agricultural and Food Chemistry (2014)

Noemi González‐Abuín Neus Martínez-Micaelo Mayte Blay Anna Ardévol Montserrat Pinent

Grape-seed procyanidin extract (GSPE) has been reported to improve insulin resistance in cafeteria rats. Because glucagon-like peptide-1 (GLP-1) is involved in glucose homeostasis, the preventive effects of GSPE on GLP-1 production, secretion, and elimination were evaluated in a model of diet-induced insulin resistance. Rats were fed a cafeteria diet for 12 weeks, and 25 mg of GSPE/kg of body weight was administered concomitantly. Vehicle-treated cafeteria-fed rats and chow-fed rats were used as controls. The cafeteria diet decreased active GLP-1 plasma levels, which is attributed to a decreased intestinal GLP-1 production, linked to reduced colonic enteroendocrine cell populations. Such effects were prevented by GSPE. In the same context, GSPE avoided the decrease on intestinal dipeptidyl-peptidase 4 (DPP4) activity and modulated the gene expression of GLP-1 and its receptor in the hypothalamus. In conclusion, the preventive treatment with GSPE abrogates the effects of the cafeteria diet on intestinal GLP-1 production and DPP4 activity.

Cafeteria

Incretin

Grape seed extract

10.1021/jf405239p

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Citations (44)

MicroRNAs Clustered within the 14q32 Locus Are Associated with Endothelial Damage and Microparticle Secretion in Bicuspid Aortic Valve Disease

Frontiers in Physiology (2017)

Neus Martínez-Micaelo Raúl Beltrán‐Debón Gerard Aragonès Marta Faiges Josep M. Alegret

Background: We previously described that PECAM+ circulating endothelial microparticles (EMPs) are elevated in bicuspid aortic valve (BAV) disease as a manifestation of endothelial damage. In this study, we hypothesized that this endothelial damage, is functionally related to the secretion of a specific pattern of EMP-associated miRNAs. Methods: We used a bioinformatics approach to correlate the PECAM+ EMP levels with the miRNA expression profile in plasma in healthy individuals and BAV patients (n = 36). In addition, using the miRNAs that were significantly associated with PECAM+ EMP levels, we inferred a miRNA co-expression network using a Gaussian graphical modeling approach to identify highly co-expressed miRNAs or miRNA clusters whose expression could functionally regulate endothelial damage. Results: We identified a co-expression network composed of 131 miRNAs whose circulating expression was significantly associated with PECAM+ EMP levels. Using a topological analysis, we found that miR-494 was the most important hub within the co-expression network. Furthermore, through positional gene enrichment analysis, we identified a cluster of 19 highly co-expressed miRNAs, including miR-494, that was located in the 14q32 locus on chromosome 14 (p = 1.9 × 10-7). We evaluated the putative biological role of this miRNA cluster by determining the biological significance of the genes targeted by the cluster using functional enrichment analysis. We found that this cluster was involved in the regulation of genes with various functions, specifically the "cellular nitrogen compound metabolic process" (p = 2.34 × 10-145), "immune system process" (p = 2.57 × 10-6), and "extracellular matrix organization" (p = 8.14 × 10-5) gene ontology terms and the "TGF-β signaling pathway" KEGG term (p = 2.59 × 10-8). Conclusions: Using an integrative bioinformatics approach, we identified the circulating miRNA expression profile associated with secreted PECAM+ EMPs in BAV disease. Additionally, we identified a highly co-expressed miRNA cluster that could mediate crucial biological processes in BAV disease, including the nitrogen signaling pathway, cellular activation, and the transforming growth factor beta signaling pathway. In conclusion, EMP-associated and co-expressed miRNAs could act as molecular effectors of the intercellular communication carried out by EMPs in response to endothelial damage.

10.3389/fphys.2017.00648

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Citations (12)

Circulating Grp78/Bip Is Increased In Patients With Obesity And Related Metabolic Disorders And Is Associated With Atherosclerosis

Atherosclerosis (2019)

Josefa Girona Cèlia Rodríguez-Borjabad Daiana Ibarretxe Joan-Carles Vallvé Raimón Ferré

10.1016/j.atherosclerosis.2019.06.402

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Citations (2)

Specific circulating microRNA signature of bicuspid aortic valve disease

Journal of Translational Medicine (2017)

Neus Martínez-Micaelo Raúl Beltrán‐Debón Isabel Baiges Marta Faiges Josep M. Alegret

We aimed to determine the circulating miRNA expression profile associated with BAV and aortic dilation to provide diagnostic and prognostic biomarkers for BAV and/or aortic dilation. We applied a miRNome-wide microarray approach using plasma samples (n = 24) from healthy tricuspid aortic valve individuals, BAV patients and BAV patients with aortic dilation to compare and identify the specific miRNAs associated with BAV and aortic dilation. In a second stage, the expression patterns of the miRNA candidates were validated by RT-qPCR in an independent cohort (n = 43). The miRNA microarray data and RT-qPCR analyses revealed that the expression levels of circulating miR-122, miR-130a and miR-486 are significantly influenced by the morphology of the aortic valve (bicuspid/tricuspid) and could be functionally involved in the regulation of TGF-β1 signalling. Furthermore, the expression pattern of miR-718 in the plasma was strongly influenced by dilation of the ascending aorta. miR-718 expression was inversely correlated with the aortic diameter (R = −0.63, p = 3.1 × 10−5) and was an independent predictor of aortic dilation (β = −0.41, p = 0.022). The genes targeted by miR-718 are involved in the regulation of vascular remodelling. We propose that miR-122, miR-130a, miR-486 and miR-718 are new molecular features associated with BAV and aortic dilation principally by the activation of TGF-β1 pathway and vascular remodelling mediated by VEGF signalling pathways.

Dilation (metric space)

10.1186/s12967-017-1176-x

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Citations (62)

Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity

Journal of Clinical Medicine (2020)

Neus Martínez-Micaelo Carme Ligero Borja Antequera-González Alexandra Junza Óscar Yanes

The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV.Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism.We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve.Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.

Dilation (metric space)

10.3390/jcm9072215

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Citations (9)

Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels—The zero-LDL hypothesis

Journal of clinical lipidology (2018)

L. Masana Josefa Girona Daiana Ibarretxe Ricardo Rodríguez‐Calvo Roser Rosales

Low-density lipoprotein

10.1016/j.jacl.2017.12.018

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Citations (61)

Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms

Biomolecules (2020)

Ricardo Rodríguez‐Calvo Sara Samino Josefa Girona Neus Martínez-Micaelo Pere Ràfols

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography-mass spectrometry (LC-MS) and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC-MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI-MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of β-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.

Lipidome

Lipogenesis

Resistin

Steatosis

10.3390/biom10091275

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Citations (11)

BMS309403 decreases fatty acid-induced endoplasmic reticulum stress-associated inflammation in skeletal muscle

Atherosclerosis (2018)

Ricardo Rodríguez‐Calvo Alba Bosquet Josefa Girona Sandra Guaita‐Esteruelas Mercedes Heras

10.1016/j.atherosclerosis.2018.06.606

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Citations (0)