Cristina M. Ramírez

IMDEA Food

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Carlos Fernández‐Hernando

Yale University

Leigh Goedeke

Icahn School of Medicine at Mount Sinai

Noemí Rotllán

Yale University

Yajaira Suárez

Yale University

Mario Dı́az

Universidad de Guanajuato

Ana Pérez-García

Universidad Complutense de Madrid

Ramón Menta

TiGenix (Spain)

Alberto Canfrán‐Duque

Yale University

Eleuterio Lombardo

TiGenix (Spain)

Rafael Alonso

Research Institute Hospital 12 de Octubre

Cooperative Institutions

Yale University

Instituto de Salud Carlos III

Universidad Autónoma de Madrid

Bellingham Technical College

Harvard University

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red

New York University

Universidad de Las Palmas de Gran Canaria

Massachusetts General Hospital

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Toll-like Receptor–Mediated Signaling in Human Adipose-Derived Stem Cells: Implications for Immunogenicity and Immunosuppressive Potential

Tissue Engineering Part A (2008)

Eleuterio Lombardo Olga DelaRosa Pablo Mancheño‐Corvo Ramón Menta Cristina M. Ramírez

Human adipose-derived stem cells (hASCs) are mesenchymal stem cells with reduced immunogenicity and the capability to modulate immune responses. These properties make hASCs of special interest as therapeutic agents in the settings of chronic inflammatory and autoimmune diseases. Exogenous and endogenous toll-like receptor (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis because of the permanent exposure of the immune system to TLR-specific stimuli. Therefore, hASCs employed in therapy are potentially exposed to TLR ligands, which may result in the modulation of hASC activity and therapeutic potency. In this study, we demonstrate that hASCs possess active TLR2, TLR3, and TLR4, because activation with specific ligands resulted in induction of nuclear factor kappa B-dependent genes, such as manganese superoxide dismutase and the release of interleukin (IL)-6 and IL-8. TLR3 and TLR4 ligands increased osteogenic differentiation, but no effect on adipogenic differentiation or proliferation was observed. Moreover, we show that TLR activation does not impair the immunogenic and immunosuppressive properties of hASCs. These results may have important implications with respect to the safety and efficacy of hASC-based cell therapies.

10.1089/ten.tea.2008.0340

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Citations (146)

Role of miR-199a-5p in the post-transcriptional regulation of ABCA1 in response to hypoxia in peritoneal macrophages

Frontiers in Cardiovascular Medicine (2022)

Juan Aranda Ana Pérez-García Marta Torrecilla-Parra Mario Fernández-de Frutos Yolanda Martín-Martín

Hypoxia is a crucial factor contributing to maintenance of atherosclerotic lesions. The ability of ABCA1 to stimulate the efflux of cholesterol from cells in the periphery, particularly foam cells in atherosclerotic plaques, is an important anti-atherosclerotic mechanism. The posttranscriptional regulation by miRNAs represents a key regulatory mechanism of a number of signaling pathways involved in atherosclerosis. Previously, miR-199a-5p has been shown to be implicated in the endocytic and retrograde intracellular transport. Although the regulation of miR-199a-5p and ABCA1 by hypoxia has been already reported independently, the role of miR-199a-5p in macrophages and its possible role in atherogenic processes such us regulation of lipid homeostasis through ABCA1 has not been yet investigated. Here, we demonstrate that both ABCA1 and miR-199a-5p show an inverse regulation by hypoxia and Ac-LDL in primary macrophages. Moreover, we demonstrated that miR-199a-5p regulates ABCA1 mRNA and protein levels by directly binding to its 3’UTR. As a result, manipulation of cellular miR-199a-5p levels alters ABCA1 expression and cholesterol efflux in primary mouse macrophages. Taken together, these results indicate that the correlation between ABCA1-miR-199a-5p could be exploited to control macrophage cholesterol efflux during the onset of atherosclerosis, where cholesterol alterations and hypoxia play a pathogenic role.

Hypoxia

10.3389/fcvm.2022.994080

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Citations (3)

Front Matter: Volume 10370

Hardeep Anand Nicolas Barreau Andreas Bemm Whit Bennett Kyo Beyeler

10.1117/12.2295643

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Citations (0)

miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice

Atherosclerosis (2015)

Leigh Goedeke Noemí Rotllán Cristina M. Ramírez Juan Aranda Alberto Canfrán‐Duque

10.1016/j.atherosclerosis.2015.09.033

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Citations (61)

Acute relaxation of mouse duodenun by estrogens

European Journal of Pharmacology (2004)

Mario Dı́az Cristina M. Ramírez Raquel Marín Jorge Marrero‐Alonso Tomás Gómez

10.1016/j.ejphar.2004.08.020

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Citations (10)

Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144

Circulation Research (2013)

Cristina M. Ramírez Noemí Rotllán Alexander V. Vlassov Alberto Dávalos Mu Li

Rationale: Foam cell formation because of excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate–binding cassette (ABC) transporters, including adenosine triphosphate–binding cassette transporter A1 (ABCA1) and adenosine triphosphate–binding cassette transporter G1 (ABCG1). ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. Objective: We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. Methods and Results: To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed an miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to apolipoproteinA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 seems to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. Conclusions: miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression and modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease.

ABCG1

Liver X receptor

Reverse cholesterol transport

High-density lipoprotein

10.1161/circresaha.112.300626

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Citations (198)

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

Diabetes (2016)

Peter Willeit Philipp Skroblin Alexander R. Moschen Xiaoke Yin Dorothee Kaudewitz

MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122–treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30–1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03–1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.

10.2337/db16-0731

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Citations (227)

VDAC and ERα interaction in caveolae from human cortex is altered in Alzheimer's disease

Molecular and Cellular Neuroscience (2009)

Cristina M. Ramírez Miriam González‐Gómez Mario Dı́az Rafael Alonso Isidró Ferrer

Voltage-dependent anion channel

VDAC1

Neurotoxicity

Caveolin

Caveolin 1

10.1016/j.mcn.2009.07.001

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Citations (89)

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

Nature Communications (2016)

Jan R. Kraehling John H. Chidlow Chitra Rajagopal Michael G. Sugiyama Joseph W. Fowler

Abstract In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr- KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.

Transcytosis

PCSK9

Endothelial Dysfunction

Probucol

10.1038/ncomms13516

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Citations (134)

Antagonism of miR-148a attenuates atherosclerosis progression in APOBApobecLdlr+/- mice: A brief report

Biomedicine & Pharmacotherapy (2022)

Noemí Rotllán Xinbo Zhang Alberto Canfrán‐Duque Leigh Goedeke Raquel Griñán

miR-148a-3p (miR-148a) is a hepatic and immune-enriched microRNA (miRNA) that regulates macrophage-related lipoprotein metabolism, cholesterol homeostasis, and inflammation. The contribution of miR-148a-3p to the progression of atherosclerosis is unknown. In this study, we determined whether miR-148a silencing mitigated atherogenesis in APOB

10.1016/j.biopha.2022.113419

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Citations (6)