Person: Gómez Hernández, María De La Almudena
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First Name
María De La Almudena
Last Name
Gómez Hernández
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
12 results
Search Results
Now showing 1 - 10 of 12
Item Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model(Cells, 2021) Gómez Hernández, María De La Almudena; Heras Jiménez, Natalia De Las; López-Pastor, Andrea R.; García-Gómez, Gema; Infante-Menéndez, Jorge; González-López, Paula; González-Illanes, Tamara; Lahera Julia, Vicente; Benito De Las Heras, Manuel R.; Escribano Illanes, ÓscarBackground: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.Item Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity(Disease models & mechanisms, 2019) Raposo López-Pastor, Andrea; Gómez Hernández, María De La Almudena; Díaz Castroverde, Sabela; González-Aseguinolaza Gloria; González Rodríguez, Águeda; García, Gema; Fernández, Silvia; Escribano Illanes, Óscar; Benito, ManuelAmong the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high fat diet-induced obesity. We addressed the role of insulin receptor isoforms on glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAV) in a mouse model of diet-induced insulin resistance and obesity. IRA expression, but not IRB, induced an increased glucose uptake in the liver and muscle improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1. Taking together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease (NAFLD) associated to obesity.Item New Mediators in the Crosstalk between Different Adipose Tissues(Int J Mol Sci, 2024) Gómez Hernández, María De La Almudena; Heras Jiménez, Natalia De Las; González Gálvez, Beatriz; Fernández-Marcelo, Tamara; Fernández Millán, Elisa; Escribano Illanes, Óscar; Frontini, AndreaAdipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.Item Oxidative Stress Modulation by ncRNAs and Their Emerging Role as Therapeutic Targets in Atherosclerosis and Non-Alcoholic Fatty Liver Disease(Antioxidants, 2023) Infante-Menéndez, Jorge; González-López, Paula; Huertas-Lárez, Raquel; Gómez Hernández, María De La Almudena; Escribano Illanes, ÓscarAtherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed.Item Concerted regulation of non-alcoholic fatty liver disease progression by microRNAs in apolipoprotein E-deficient mice(Disease Models & Mechanisms, 2021) López-Pastor, Andrea R.; Infante-Menéndez, Jorge; González-Illanes, Tamara; González-López, Paula; González-Rodríguez, Águeda; García-Monzón, Carmelo; Vega de Céniga, Melina; Esparza, Leticia; Gómez Hernández, María De La Almudena; Escribano Illanes, ÓscarThe prevalence of non-alcoholic fatty liver disease (NAFLD) is constantly increasing, and altered expression of microRNAs (miRNAs) fosters the development and progression of many pathologies, including NAFLD. Therefore, we explored the role of new miRNAs involved in the molecular mechanisms that trigger NAFLD progression and evaluated them as biomarkers for diagnosis. As a NAFLD model, we used apolipoprotein E-deficient mice administered a high-fat diet for 8 or 18 weeks. We demonstrated that insulin resistance and decreased lipogenesis and autophagy observed after 18 weeks on the diet are related to a concerted regulation carried out by miR-26b-5p, miR-34a-5p, miR-149-5p and miR-375-3p. We also propose circulating let-7d-5p and miR-146b-5p as potential biomarkers of early stages of NAFLD. Finally, we confirmed that circulating miR-34a-5p and miR-375-3p are elevated in the late stages of NAFLD and that miR-27b-3p and miR-122-5p are increased with disease progression. Our results reveal a synergistic regulation of key processes in NAFLD development and progression by miRNAs. Further investigation is needed to unravel the roles of these miRNAs for developing new strategies for NAFLD treatment.Item Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet–induced obesity and its metabolic complications in male mice(Molecular metabolism, 2020) Gómez Hernández, María De La Almudena; Raposo López-Pastor, Andrea; Rubio-Longas, Carlota; Majewski, Patrik; Beneit, Nuria; Viana-Huete, Vanesa; García-Gómez, Gema; Fernandez, Silvia; Hribal, Marta Letizia; Sesti, Giorgio; Escribano Illanes, Óscar; Benito De Las Heras, Manuel R.Objective: An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85a in BAT (BATp85aKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications. Methods: We generated BATp85aKO mice using Cre-LoxP technology, specifically deleting p85a in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85aKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality. Results: Our results suggest that the loss of p85a in BAT improves its thermogenic functionality, high-fat dieteinduced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis. Conclusions: Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85a has a direct impact on the prevention of diet-induced obesity and its associated metabolic complicationsItem Role of miR‐15a‐5p and miR‐199a‐3p in the inflammatory pathway regulated by NF‐κB in experimental and human atherosclerosis(Clinical and Translational Medicine, 2023) González‐López, Paula; Álvarez‐Villarreal, Marta; Ruiz‐Simón, Rubén; Raposo López‐Pastor, Andrea; Vega de Ceniga, Melina; Esparza, Leticia; Martín‐Ventura, José L.; Gómez Hernández, María De La Almudena; Escribano Illanes, ÓscarBackground: Cardiovascular diseases (CVDs) prevalence has significantlyincreased in the last decade and atherosclerosis development is the main trig-ger. MicroRNAs (miRNAs) are non-coding RNAs that negatively regulate geneexpression of their target and their levels are frequently altered in CVDs. Methods: By RT-qPCR, we analysed miR-9-5p, miR-15a-5p, miR-16-5p andmiR-199a-3p levels in aorta from apolipoprotein knockout (ApoE−/−) mice, anexperimental model of hyperlipidemia-induced atherosclerosis, and in humanaortic and carotid atherosclerotic samples. By in silico studies, Western blotanalysis and immunofluorescence studies, we detected the targets of the alteredmiRNAs. Results: Our results show that miR-15a-5p and miR-199a-3p are significantlydecreased in carotid and aortic samples from patients and mice with atheroscle-rosis. In addition, we found an increased expression in targets of both miRNAsthat participate in the inflammatory pathway of nuclear factor kappa B (NF-κB), such as IKKα,IKKβand p65. In human vein endothelial cells (HUVECs)and vascular smooth muscle cells (VSMCs), the overexpression of miR-15a-5p ormiR-199a-3p decreased IKKα,IKKβand p65 protein levels as well as NF-κB acti-vation. On the other hand, miR-15a-5p and miR-199a-3p overexpression reducedox-LDL uptake and the inflammation regulated by NF-κB in VSMCs. Moreover,although miR-15a-5p and miR-199a-3p were significantly increased in exosomes from patients with advanced carotid atherosclerosis, only in the ROC analysesfor miR-15a-5p, the area under the curve was 0.8951 with apvalue of .0028. Conclusions: Our results suggest that the decrease of miR-199a-3p and miR-15a-5p in vascular samples from human and experimental atherosclerosis could beinvolvedintheNF-κBactivationpathway,aswellasinox-LDLuptakebyVSMCs,contributing to inflammation and progression atherosclerosis. Finally, miR-15a-5p could be used as a novel diagnostic biomarker for advanced atherosclerosis.Item Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis(Liver International, 2023) Infante‐Menéndez, Jorge ; López‐Pastor, Andrea R. ; González‐Illanes, Tamara ; González‐López, Paula ; Huertas‐Lárez, Raquel ; Rey, Esther ; González‐Rodríguez, Águeda; García‐Monzón, Carmelo; Patil, Nikita P.; Vega De Céniga, Melina ; Baker, Aaron B.; Gómez Hernández, María De La Almudena; Escribano Illanes, ÓscarBackground and Aims: The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d- 5p could contribute to the pathophysiol-ogy of NAFLD and serve as a potential diagnostic biomarker.Methods: We evaluated let-7d- 5p levels and its targets in liver biopsies from a cross- sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d- 5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d- 5p in vitro to corroborate the results observed in vivo. Circulating let-7d- 5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR.Results: Our results demonstrate that hepatic let-7d- 5p was significantly up- regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin- like growth factor 1 (IGF1), IGF- I receptor (IGF1R) and insulin receptor (INSR). These alterations were corrobo-rated in a NAFLD mouse model. In vitro, fatty acids increased let-7d- 5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let- 7d- 5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, cir-culating let-7d- 5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker.Item Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque(International Journal of Molecular Sciences, 2022) González-López, Paula; Ares-Carral, Carla; López-Pastor, Andrea R.; Infante-Menéndez, Jorge; González Illanes, Tamara; Vega de Ceniga, Melina; Esparza, Leticia; Beneit, Nuria; Martín-Ventura, José Luis; Escribano Illanes, Óscar; Gómez Hernández, María De La Almudena(1) Background: Cardiovascular diseases (CVDs) are the main cause of death in developed countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) modulate the expression of their targets and have emerged as key players in CVDs; (2) Methods: 18 miRNAs were selected (Pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from apolipoprotein E-deficient (ApoE−/−) mice. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE−/− mice were studied in human aortic and carotid samples; (3) Results: miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease in protein kinase B (AKT), target of miR-155-5p, and an increase in insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE−/− mice and in carotid plaques from patients with advanced carotid atherosclerosis (ACA). Finally, the overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells, while miR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells; (4) Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of atherosclerosis.Item Potential protective role of let-7d-5p in atherosclerosis progression reducing the inflammatory pathway regulated by NF-κB and vascular smooth muscle cells proliferation(Biochim Biophys Acta Mol Basis Dis, 2024) Aroca-Esteban, Javier; Souza-Neto, Francisco V.; Aguilar-Latorre, Carlota; Tribaldo-Torralbo, Alba; González-López, Paula; Ruiz-Simón, Rubén; Álvarez-Villareal, Marta; Ballesteros, Sandra; Vega de Ceniga, Melina; Landete, Pedro; González-Rodríguez, Águeda; Martín-Ventura, José L; Heras, Natalia de Las; Escribano Illanes, Óscar; Gómez Hernández, María De La AlmudenaThe prevalence of cardiovascular diseases (CVDs) is increasing in the last decades, even is the main cause of death in first world countries being atherosclerosis one of the principal triggers. Therefore, there is an urgent need to decipher the underlying mechanisms involved in atherosclerosis progression. In this respect, microRNAs dysregulation is frequently involved in the progression of multiple diseases including CVDs. Our aim was to demonstrate that let-7d-5p unbalance could contribute to the pathophysiology of atherosclerosis and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels in vascular biopsies and exosome-enriched extracellular vesicles (EVs) from patients with carotid atherosclerosis and healthy donors. Moreover, we overexpressed let-7d-5p in vitro in vascular smooth muscle cells (VSMCs) to decipher the targets and the underlying mechanisms regulated by let-7d-5p in atherosclerosis. Our results demonstrate that let-7d-5p was significantly upregulated in carotid plaques from overweight patients with carotid atherosclerosis. Moreover, in EVs isolated from plasma, we found that let-7d-5p levels were increased in carotid atherosclerosis patients compared to control subjects specially in overweight patients. Receiver Operating Characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker for atherosclerosis. In VSMCs, we demonstrated that increased let-7d-5p levels impairs cell proliferation and could serve as a protective mechanism against inflammation by impairing NF-κB pathway without affecting insulin resistance. In summary, our results highlight the role of let-7d-5p as a potential therapeutic target for atherosclerosis since its overexpression induce a decrease in inflammation and VSMCs proliferation, and also, as a novel non-invasive diagnostic biomarker for atherosclerosis in overweight patients.