Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19605

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The transcription factor NF-Y promotes myeloid cell survival and protects from inflammatory vascular disease.
(OXFORD UNIV PRESS, 2026-08-27) Silvestre-Roig, Carlos; González-Granado, José M; Osei-Sarpong, Collins; Gricar, Eva; Gonzalo, Pilar; Farjia, Merieme; Malamud, Mariano; Vöcking, Lina-Marie; Alonso-Gonzalez, Noelia; Chevre, Raphael; Esteban, Vanesa; Andrés, Vicente
Myeloid cells orchestrate vascular inflammation through transcriptional programs that control their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, our understanding of the transcriptional regulation of myeloid cell behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation and is essential for maintaining stem and progenitor cell fitness. Here, we investigate NF-Y activity in myeloid cell function and survival using integrated single-cell transcriptomics and myeloid-specific deletion of the NF-YA subunit. At RNA level, NF-Y subunit transcripts were detected across myeloid compartments, with NF-YA enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low NF-YA levels were associated with macrophages exhibiting lipid-handling and phagocytic signatures and with neutrophils displaying a proinflammatory phenotype. NF-Y deficiency impaired neutrophil adhesion and rolling, increased their susceptibility to apoptosis, and promoted activation and lipid accumulation in macrophages. In vivo, myeloid NF-YA deficiency reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, leading to larger and more unstable atherosclerotic lesions, and aggravated both atherosclerosis and injury-induced neointimal thickening. These findings identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.
Quality standards for preclinical research in cardio-oncology.
(OXFORD UNIV PRESS, 2026-09-07) Ameri, Pietro; Madonna, Rosalinda; Costa, Ambra; Amit, Uri; Andreadou, Ioanna; Asnani, Aarti; Burridge, Paul W; Balbi, Carolina; De Keulenaer, Gilles W; Evans, Paul C; Ghigo, Alessandra; Ibáñez, Borja; Lehmann, Lorenz H; Martín, Pilar; Minotti, Giorgio; Meijers, Wouter C; Morel, Eric; Ngo, Doan; Rhee, June-Wha; Remme, Carol Ann; Tocchetti, Carlo Gabriele; van Der Meer, Peter; Varga, Zoltán V; Verginadis, Ioannis I; Walls, Gerard M; Wojta, Johann; López Fernández, Teresa
Preclinical research in cancer therapy-related cardiovascular toxicity (CTR-CVT) is a major domain of cardio-oncology and has provided biological explanation for the cardiovascular adverse effects of many cancer therapies. However, the choice of the experimental models to investigate the mechanisms of CTR-CVT is often based on personal experience and opinion, rather than on established principles and available evidence. Moreover, presentation of methods and results is frequently approximate. This Scientific Statement outlines potential quality standards regarding methodology and reporting in preclinical cardio-oncology research, with the goal of promoting accurate, reliable, and reproducible studies. Quality standards are distinguished in first-tier, when considered essential for robustness unless there is a strong justification for their omission, and second-tier standards, when desirable, but not necessary. First-tier standards ensure credible, self-sustaining research, while second-tier ones enhance quality of investigations and accelerate understanding of CTR-CVT. Adherence to the proposed quality standards is expected to benefit researchers embarking on new investigations, facilitate funding allocation, and inform the development of novel oncological therapies, eventually moving cardio-oncology science forward.
No Effect of -Mutant Clonal Hematopoiesis on Atherosclerosis Development in Mice.
(Lippincott Williams & Wilkins (LWW), 2026-07) Amorós-Pérez, Marta; Zuriaga, María A; Zorita, Virginia; Ramos-Neble, Beatriz L; Matesanz, Nuria; Plötner, Clara; Di Carli, Milena; Mol, Eline L C; Moro, Rosa; Cuevas, Diego; Andrés, Vicente; Fuster, José J
BACKGROUND: Clonal hematopoiesis driven by somatic mutations is an emerging cardiovascular risk factor, and the DNA damage response gene is among the most frequently mutated genes. Mutations in are enriched in cancer patients and survivors, where cytotoxic therapies promote the expansion of mutant clones, a condition termed therapy-related clonal hematopoiesis. Although -mutant clonal hematopoiesis has been associated with increased risk and poorer prognosis of atherosclerotic cardiovascular disease in humans, it remains unclear whether these mutations, or their expansion under cytotoxic stress, causally contribute to atherosclerosis. METHODS: We modeled -mutant clonal hematopoiesis in mice through bone marrow transplantation strategies. Conventional transplantation approaches were used to generate mice with complete or partial hematopoietic reconstitution by cells carrying monoallelic or biallelic gain-of-function mutations. To mimic therapy-related clonal hematopoiesis, we used a nonconditioned adoptive transfer model in which a small fraction of mutant hematopoietic cells was introduced into recipients, followed by fractionated low-dose γ-radiation to promote clonal expansion. All mice were fed a Western diet to induce atherosclerosis. Clonal dynamics, plaque size and characteristics, and macrophage functions were evaluated using flow cytometry, histopathology, and in vitro assays. RESULTS: -mutant cells expanded in blood and bone marrow after low-dose radiation, but not in nonirradiated mice. Across all transplantation strategies, mutations did not affect plasma cholesterol, atherosclerotic plaque size, or composition. In vitro, mutant macrophages showed no alterations in proliferation, cytokine expression, or cholesterol handling, although apoptosis in response to genotoxic stress was modestly reduced (≈20%). CONCLUSIONS: -mutant hematopoietic cells expand predominantly under genotoxic stress and do not promote atherosclerosis in mice under the conditions tested. These findings raise the possibility that the association of mutations with atherosclerotic cardiovascular disease may, at least in part, reflect exposure to DNA damage response-activating stressors that independently promote clonal expansion and atherosclerosis, rather than direct causality.
Telomere length dynamics do not predict subclinical atherosclerosis progression over a six-year period.
(SPRINGER, 2026-05-27) Andrés, Vicente; Fernández-Alvira, Juan M; Dorado, Beatriz; Guío-Carrión, Ana; García-Álvarez, Ana; García-Lunar, Inés; Fernández-Ortiz, Antonio; Fuster, José J; Pocock, Stuart; Ibáñez, Borja; Blasco, María A; Fuster, Valentín
Subclinical atherosclerosis (SA) burden and progression are independently associated with all-cause mortality. However, monitoring SA progression requires reliable and cost-effective biomarkers. While leukocyte telomere length (LTL) attrition has been linked to cardiovascular disease and mortality, it remains uncertain whether changes in LTL over time can predict SA progression. In this study, we conducted a longitudinal study to assess whether accelerated LTL attrition is associated with SA progression over a 6-year period in healthy middle-aged individuals. LTL was measured by high-throughput quantitative fluorescence in-situ hybridization in peripheral-blood leukocyte samples obtained 6 years apart from a sub-cohort of 1068 Progression of Early Subclinical Atherosclerosis (PESA)-study participants. SA was assessed by 3D vascular ultrasound in the carotid and femoral territories. Associations were evaluated using linear and logistic regression models. LTL parameters at baseline and after 6 years showed a positive correlation, but no significant associations were found between changes in LTL and changes in plaque volume over 6 years, either in the total sample or when stratified by sex. Likewise, no significant associations were found between LTL changes and the odds of SA progression over a 6-year period. Similar results were found when considering short telomere load changes. These findings suggest limited utility of LTL dynamics as an early biomarker for SA progression in healthy middle-aged individuals.
Host determinants of exo-rAAV production revealed by extended gene expression analysis in HEK293 cells.
(2026-09-10) Lavado-García, Jesús; Bosch-Molist, Laia; Ruiz-Ayala, Carlos; Jorge, Inmaculada; Vázquez, Jesús; Gòdia, Francesc; Cervera, Laura
Recombinant adeno-associated viruses (rAAVs) are leading vectors for gene therapy, yet their large-scale manufacturing remains constrained by low scalability and high costs. Here, we present an integrated systems biology and process engineering strategy to intensify rAAV production through the extended gene expression (EGE) methodology. EGE has been reported to significantly increase rAAV yields, enhanced viral egress, and promote the secretion of exosome-associated AAVs (exo-AAVs), resulting in higher extracellular titers and improved vector potency. Quantitative multiplexed proteomics revealed coordinated remodeling of host-cell pathways involved in vesicle trafficking, lipid biosynthesis, protein homeostasis, and nuclear transport. Functional validation identified key host regulators of exo-rAAV biogenesis and secretion, including CD63, VPS37B, SMPD3, and SNAP47. Targeted modulation of these pathways enabled rational enhancement of extracellular rAAV recovery in standard batch processes. Using a DoE-based mixture design, we achieved 50% viral egress into the supernatant, with >21% being exo-AAVs, demonstrating efficient translation of the EGE phenotype into scalable batch manufacturing. Collectively, this work provides a scalable and cost-effective alternative production platform with the advantages of the EGE methodology. These findings can help advance next-generation rAAV manufacturing and support the development of gene therapy vectors.
Hematopoyetic deficiency in polymeric immunoglobulin receptor attenuates experimental atherosclerosis.
(ELSEVIER, 2026-07-25) Cerro-Pardo, Isabel; Picatoste, Belén; Márquez-Gálvez, Cristina; Ortega-Villanueva, Lucía; Escolà-Gil, Joan Carles; Núñez, Estefanía; Vázquez, Jesús; Blanco-Colio, Luis Miguel; Martín-Ventura, José Luis
Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein involved in the transcytosis of polymeric IgA and IgM immunoglobulins. Recent data from our group described that systemic deficiency of Pigr reduces atherosclerosis development, which is associated with increased plasma IgA and IgM levels. To analyse the role of Pigr deficiency in hematopoietic cells in an experimental model of atherosclerosis in mice. We analyzed PIGR distribution in early atherosclerotic plaques compared to healthy aortic samples, as well as PIGR expression in macrophages derived from human peripheral blood mononuclear cells (PBMCs). The contribution of hematopoietic Pigr to experimental atherosclerosis was assessed by performing bone marrow transplantation in Ldlr mice fed an atherogenic diet for 10weeks. PIGR expression was observed in the intima of early human atherosclerotic lesions, showing colocalization with macrophages. In addition, PIGR levels increased during the in vitro differentiation of human PBMCs into macrophages. Analysis of the hematopoietic lineage-specific Pigr deficiency in atherosclerosis revealed that Pigr mice displayed significantly reduced plaque size in the aortic sinuses as well as a strong decrease in macrophage infiltration, while no changes in contractile vascular smooth muscle cells and collagen content were observed. These effects occurred independently of systemic changes in lipids, IgA and IgM levels. Hematopoietic Pigr deficiency attenuates experimental atherosclerosis, although the molecular mechanisms underlying this protective effect remain to be fully elucidated.
Atherosclerosis antigens as targets for immunotherapy.
(SPRINGERNATURE, 2023-12) Raposo-Gutiérrez, Irene; Rodríguez-Ronchel, Ana; Ramiro, Almudena R
Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction and stroke, underlying the first cause of mortality worldwide. Adaptive immunity plays critical roles in atherosclerosis, and numerous studies have ascribed both atheroprotective and atherogenic functions to specific subsets of T and B cells. However, less is known on how antigen specificity determines the protective or adverse outcome of such adaptive responses. Understanding antigen triggers in atherosclerosis is crucial to delve deeper into mechanisms of disease initiation and progression and to implement specific immunotherapeutic approaches, including vaccination strategies. Here we review the role of adaptive immunity in atherosclerosis and the insights that single-cell technology has provided into the function of distinct immune cell subsets. We outline the most relevant atherosclerosis antigens and antibodies reported to date and examine their immunotherapeutic potential. Finally, we review the most promising vaccination-based clinical trials targeting the adaptive immune system.
HIF-1α and HIF-2α differentially regulate alveolar macrophage maturation and function.
(CELL PRESS, 2026-06-23) Priego, Elena; Adan-Barrientos, Irene; Conde-Garrosa, Ruth; Martínez-Cano, Sarai; Sánchez, Iria; Mañanes, Diego; Mastrangelo, Annalaura; Amores-Iniesta, Joaquín; Izquierdo, Helena M; Sancho, David
Alveolar macrophages (AMs) reside in the oxygen-rich alveoli, where hypoxia-inducible transcription factor (HIF) subunits are targeted for degradation by the Von Hippel-Lindau protein (pVHL). We previously showed that Vhl-deficient AMs are immature and functionally impaired. Here, we define isoform-specific roles of HIF-1α and HIF-2α in the regulation of AM maturation and function. Expression of either isoform alone is sufficient to intrinsically, and differentially, impair AM terminal maturation and self-renewal, with complete rescue observed only when both HIF-1α and HIF-2α are deleted in Vhl-deficient AMs. HIF-1α drives glycolytic reprogramming in AMs, while HIF-2α disrupts fatty acid oxidation and surfactant clearance. Consequently, HIF-2α stabilization limits the capacity of AMs to resolve surfactant excess in a mouse model of pulmonary alveolar proteinosis, indicating HIF-2α as a potential therapeutic target. Overall, HIF inactivation ensures optimal AM maturation and metabolic adaptation to the high-oxygen alveolar niche, revealing non-redundant functional specificities of each HIF-α isoform.
Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
(AMER ASSOC ADVANCEMENT SCIENCE, 2026-05-29) Khouili, Sofía C; Priego, Elena; Heras-Murillo, Ignacio; Dunphy, Gillian; Mastrangelo, Annalaura; Martínez-Cano, Sarai; Nuñez, Vanessa; Rodrigo-Tapias, Manuel; Belinchón-García, Adrián; Garaude, Johan; Iborra, Salvador; Chandel, Navdeep S; González-Rodríguez, Patricia; Enamorado, Michel; Sancho, David
Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD-driven redox metabolism, and antigen cross-presentation.
Improved Protein Identification in Shotgun Proteomics with a Group-Level Extension of the LPGF Model.
(AMER CHEMICAL SOC, 2026-08-07) Prieto, Gorka; Vázquez, Jesús
Shotgun proteomics relies on robust statistical methods to increase the confidence of the protein identifications. Previously, we introduced LPGF, a protein probability model based on unique peptides. In this study, we extend LPGF to protein groups that share peptides by considering only peptides that are unique to each group. This strategy preserves the principle of unique evidence while enabling the probability estimation at the protein-group level. Applying our method to three tissues from the Human Proteome Map (HPM), we evaluated the gain in protein identifications obtained with group-unique peptides compared to those obtained using only protein-unique peptides and different scores. The accuracy of false discovery rate (FDR) estimation was further validated using a standard data set for protein inference based on human Protein Epitope Signature Tags (PrESTs), as well as through an entrapment experiment using the substantially larger HPM data set. To facilitate adoption, we developed an R package (b10prot) that integrates the full workflow, including protein-level and group-level LPGF score computation and protein grouping via an R port of our previous tool PAnalyzer. Our results demonstrate that extending LPGF to protein groups increases sensitivity while maintaining robust FDR control, thus providing the proteomics community with a practical framework for more comprehensive protein identification.
Technologies to Study Genetics and Molecular Pathways.
(SPRINGER INTERNATIONAL PUBLISHING AG, 2024) Grunert, Marcel; Dorn, Cornelia; Dopazo, Ana; Sánchez-Cabo, Fátima; Vázquez, Jésus; Rickert-Sperling, Silke; Lara-Pezzi, Enrique
Over the last few decades, the study of congenital heart disease (CHD) has benefited from various model systems and the development of molecular biological techniques enabling the analysis of single gene as well as global effects. In this chapter, we first describe different models including CHD patients and their families, animal models ranging from invertebrates to mammals, and various cell culture systems. Moreover, techniques to experimentally manipulate these models are discussed. Second, we introduce cardiac phenotyping technologies comprising the analysis of mouse and cell culture models, live imaging of cardiogenesis, and histological methods for fixed hearts. Finally, the most important and latest molecular biotechniques are described. These include genotyping technologies, different applications of next-generation sequencing, and the analysis of transcriptome, epigenome, proteome, and metabolome. In summary, the models and technologies presented in this chapter are essential to study the function and development of the heart and to understand the molecular pathways underlying CHD.
OMA1 protects from liver injury and tumorigenesis during aging by controlling hepatic immunogenicity.
(SPRINGERNATURE, 2026-06-23) Martí-Mateos, Yolanda; Muñoz-Hernández, María Del Mar; Gómez de Las Heras, Manuel M; Escrig-Larena, José Ignacio; Cabrera-Alarcón, José Luis; Acín-Pérez, Rebeca; Calvo, Enrique; Jaroszewicz, Sara Natalia; de Prado-Rivas, Lucía; Martínez-Jiménez, Eva Raquel; De Andrés-Laguillo, Macarena; García-Domínguez, Esther; Gómez-Cabrera, María Carmen; Viña, José; Benedito, Rui; Efeyan, Alejo; Vázquez, Jesús; Mittelbrunn, María; Jiménez-Gómez, María Concepción; Enríquez, José Antonio
Hepatic inflammation and immunosurveillance play major roles in the progression of liver cancer. A common trigger for hepatic inflammation is oxidative stress, which stems from mitochondrial dysfunction. Here, we demonstrate that deletion of the mitochondrial stress integrator OMA1 increases hepatic primary tumor incidence and impairs survival in mice. Persistent activation of the KEAP1-Nrf2 oxidative stress pathway in the absence of OMA1 promotes early liver injury, which progresses into chronic hepatic inflammation and fibrosis during aging. Exhausted CD8 and CD4 T cells gradually accumulate in Oma1 livers, facilitating hepatic tumor progression. Adoptive transfer and bone marrow-transplant experiments indicate that hepatic immunogenicity increases in the absence of parenchymal OMA1. Furthermore, hepatocyte-specific Oma1 deletion is sufficient to trigger NRF2 signaling, hepatocyte death, and immune exhaustion, suggesting that immunosurveillance during liver aging relies on the hepatic expression of OMA1. Given the therapeutic interest of OMA1 in several pathologies, these data are crucial to guide the generation of safe OMA1-targeted therapies.
Cardiac Macrophages and Fibroblasts Modulate Atrial Fibrillation Maintenance.
(LIPPINCOTT WILLIAMS & WILKINS, 2026-03-13) Simon-Chica, Ana; Quintanilla, Jorge G; Torroja, Carlos; Couselo-Seijas, Marinela; Toda, Haruka; Lee, Peter; Benguria, Alberto; Revilla, Concepción; Redondo-Rodríguez, Andrés; Alfonso-Almazán, José Manuel; García-Escolano, Alba; Marina-Breysse, Manuel; Galán-Arriola, Carlos; Vera-Pedrosa, María Linarejos; La Rosa, Giulio; Dopazo, Ana; Sánchez-Cabo, Fátima; García-Torrent, María Jesús; Ortega-Hernández, Adriana; Ibáñez, Borja; Núñez, Estefanía; Gómez-Garre, Dulcenombre; Morillo, Carlos; Greiner, Joachim; Kohl, Peter; Pérez-Villacastín, Julián; Pérez-Castellano, Nicasio; Jalife, José; Domínguez, Javier; Vázquez, Jesús; Carnero-Alcázar, Manuel; Filgueiras-Rama, David
Nonmyocytes may contribute to regional adaptive changes during persistent atrial fibrillation (PsAF), favoring its perpetuation. We aimed to investigate the differential features of fibroblast and macrophage populations within individual-specific atrial regions associated with PsAF maintenance. The study was conducted in 2 pig models of PsAF with and without infarct-related substrate (N=27 and N=27, respectively) and further validated in humans with PsAF (N=20). Sham-operated pigs (N=9), healthy animals (N=4), and patients in sinus rhythm (N=7) were used as comparative controls. In pigs, in vivo high-density instantaneous frequency modulation maps were used to identify atrial regions associated with PsAF maintenance (drivers). Regional cellular composition and phenotypic states of fibroblast and myeloid lineages were determined using flow cytometry, single-cell RNA sequencing, immunohistochemistry, and proteomic analyses. The functional relevance of driver regions was further studied in patients with symptomatic PsAF undergoing ablation. Flow cytometry and single-cell RNA sequencing analyses were performed in tissue samples of the left atrial appendage in a complementary cohort of patients with PsAF undergoing thoracoscopic-guided ablation. PsAF terminated acutely in 12 of 14 pigs undergoing mapping and ablation of driver regions. In humans, driver ablation was associated with 90% AF-freedom (on/off antiarrhythmic drugs) after 2 years of follow-up. Samples from nonablated pigs revealed a phenotypic shift towards ACTA2 (actin alpha 2)-fibroblasts and PTX3 (pentraxin 3)-fibroblasts during PsAF. Although ACTA2-fibroblasts were highly preserved in human samples, paired comparisons in pig samples showed that PTX3-fibroblasts were enriched only in driver regions. PsAF also showed changes in myeloid cells towards inflammatory profiles. However, regional analysis revealed that, in both humans and pigs with PsAF, driver regions were enriched in cardiac resident macrophages with transcriptomic and proteomic profiles favoring cardiomyocyte homeostasis and cell survival. PsAF shows differential regional changes in fibroblast and myeloid populations with distinctive gene signatures in areas that drive the overall arrhythmia.
Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy.
(SPRINGERNATURE, 2026-07) Sen-Martín, Laura; Fernández-Trasancos, Ángel; López-Unzu, Miguel Á; Bak, Agata; Zafra-Castellano, Magdalena; Srikantharajah, Rajiven; Pathak, Divya; Klotz, Annika; Kuehn, Michel N; Ferrarini, Alessia; Labrador-Cantarero, Verónica; Sánchez-Ortiz, David; Pricolo, María Rosaria; Vicente, Natalia; Velázquez-Carreras, Diana; Sánchez-García, Lucía; Sicilia, Jon; Nicolás-Ávila, José Ángel; Sánchez-Díaz, María; Schlossarek, Saskia; Cussó, Lorena; Desco, Manuel; Villalba-Orero, María; Guzmán-Martínez, Gabriela; Calvo, Enrique; Barriales-Villa, Roberto; Vázquez, Jesús; Sánchez-Cabo, Fátima; Hidalgo, Andrés; de Tombe, Pieter P; Carrier, Lucie; Spudich, James A; Ruppel, Kathleen M; Weinberger, Florian; Cazorla, Olivier; Hessel, Anthony L; Alegre-Cebollada, Jorge
Mavacamten is a targeted treatment for hypertrophic cardiomyopathy, a disease caused by genetic variants affecting mainly sarcomeric myosin and its regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here we generate knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which unlike carriers of cMyBP-C truncations, develop pathogenic myocardial remodeling with preserved cMyBP-C levels and localization. Mechanistically, R502W reduces cMyBP-C-myosin affinity and generates sarcomere hypercontractility due to increased Ca sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating MYBPC3 variants, mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient hearts, correlating with the drug's ability to restore OFF myosin in R502W sarcomeres. In R502W human engineered heart tissues, mavacamten also opposes hypercontractility. Hence, our results indicate that mavacamten is effective in treating hypertrophic cardiomyopathy caused by both truncating and missense MYBPC3 variants regardless of their primary pathomechanisms.
RNF126 and BRAP safeguard genome integrity after DNA damage in late mitosis.
(CELL PRESS, 2026-04-16) Ayra-Plasencia, Jessel; Jorge, Inmaculada; Vázquez, Jesús; Freire, Raimundo; Smits, Veronique A J
DNA double-strand breaks generated during mitosis are thought to be inefficiently repaired, yet cellular responses to damage incurred specifically in late mitosis remain poorly understood. Here, we report that irradiation of cells synchronized in anaphase/telophase triggers partial DNA damage signaling, marked by H2AX phosphorylation and MDC1 accumulation. Consequently, cells enter G1 and S phases with unrepaired lesions. Proteomic analysis identified the E3 ubiquitin ligases RNF126 and BRAP as key regulators of this response, based on their selective ATM-dependent accumulation in irradiated late mitotic cells. Functional assays reveal that both proteins are required for damage-induced 53BP1 and RPA2 focus formation, resolution of DNA lesions, and survival after damage in late mitosis. Supporting their clinical relevance, both E3 ligases are overexpressed in selected tumors and associated with chromosomal instability. These findings suggest that RNF126 and BRAP help cells tolerate late mitotic damage and may represent potential vulnerabilities for improving genotoxic therapies in cancer.
Polymeric immunoglobulin receptor deficiency attenuates experimental atherosclerosis.
(FRONTIERS MEDIA, 2026) Cerro-Pardo, Isabel; Picatoste, Belén; Raposo-Gutiérrez, Irene; Martos-Folgado, Inmaculada; Márquez-Gálvez, Cristina; García-García, Ana; Ortega-Villanueva, Lucía; Mur, Sonia M; Robles-Vera, Iñaki; Escolà-Gil, Joan Carles; Núñez, Estefanía; Sancho, David; Lindholt, Jes; Vázquez, Jesús; Blanco-Colio, Luis Miguel; Ramiro, Almudena R; Martín-Ventura, José Luis
Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein widely expressed in mucosal epithelial cells that is involved in the transcytosis of the polymeric immunoglobulins IgA and IgM. Recent findings revealed increased plasma PIGR levels in subjects with subclinical atherosclerosis, although its function remains uncertain. To assess the role of PIGR in atherosclerosis. We analyzed PIGR levels in human atherosclerotic plaques compared to healthy aortic samples, as well as in the serum of subjects with peripheral arterial disease (PAD) and controls. Next, we studied the effect of germline deficiency in experimental atherosclerosis ( mice fed a western-diet for 10 weeks). Circulating IgA and IgM levels, as well as B and T cell numbers in spleen and Peyer's patches (PP), were analyzed by ELISA and flow cytometry, respectively. PIGR levels were increased in the intima of early human atherosclerotic lesions and in patients with PAD, compared to controls. mice showed elevated serum IgA and IgM levels, along with an increased number of germinal center B cells in both the spleen and PP. Moreover, mice displayed a significantly reduced plaque size in the aortic sinus and a strong decrease in foam cells (CD68), while no changes were observed in contractile smooth muscle cells (α-actin) and collagen content compared to control mice. Global deficiency decreases atherosclerosis, suggesting that PIGR blockade may have beneficial effects in vascular pathologies.
p38α kinase governs muscle strength through PGC1α in mice.
(WILEY, 2024-11) Herrera-Melle, Leticia; Cicuéndez, Beatriz; López, Juan Antonio; Dumesic, Phillip A; Wilensky, Sarah E; Rodríguez, Elena; Leiva-Vega, Luis; Caballero, Ainoa; León, Marta; Vázquez, Jesús; Spiegelman, Bruce M; Folgueira, Cintia; Mora, Alfonso; Sabio, Guadalupe
Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness. We conducted our study using male mice (MCK-cre, p38α and PGC1α ) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples. Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology. This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.
Cardiovascular Risk Stratification Based on Oxidative Stress for Early Detection of Pathology.
(SAGE PUBLICATIONS INC, 2021-09) Corbacho-Alonso, Nerea; Baldán-Martín, Montserrat; López, Juan Antonio; Rodríguez-Sánchez, Elena; Martínez, Paula J; Mourino-Alvarez, Laura; Sastre-Oliva, Tamara; Cabrera, Martha; Calvo, Eva; Padial, Luis R; Vázquez, Jesús; Vivanco, Fernando; Alvarez-Llamas, Gloria; Ruiz-Hurtado, Gema; Ruilope, Luis M; Barderas, Maria G
Current cardiovascular (CV) risk prediction algorithms are able to quantify the individual risk of CV disease. However, CV risk in young adults is underestimated due to the high dependency of age in biomarker-based algorithms. Because oxidative stress is associated with CV disease, we sought to examine CV risk stratification in young adults based on oxidative stress to approach the discovery of new markers for early detection of pathology. Young adults were stratified into (i) healthy controls, (ii) subjects with CV risk factors, and (iii) patients with a reported CV event. Plasma samples were analyzed using FASILOX, a novel approach to interrogate the dynamic thiol redox proteome. We also analyzed irreversible oxidation by targeted searches using the Uniprot database. Irreversible oxidation of cysteine (Cys) residues was greater in patients with reported CV events than in healthy subjects. These results also indicate that oxidation is progressive. Moreover, we found that glutathione reductase and glutaredoxin 1 proteins are differentially expressed between groups and are proteins involved in antioxidant response, which is in line with the impaired redox homeostasis in CV disease. This study, for the first time, describes the oxidative stress (reversible and irreversible Cys oxidation) implication in human plasma according to CV risk stratification. The identification of redox targets and the quantification of protein and oxidative changes might help to better understand the role of oxidative stress in CV disease, and aid stratification for CV events beyond traditional prognostic and diagnostic markers. . 35, 602-617.
Characterization of HIV-1 virus-like particles and determination of Gag stoichiometry for different production platforms.
(WILEY, 2021-07) Lavado-García, Jesús; Jorge, Inmaculada; Boix-Besora, Arnau; Vázquez, Jesús; Gòdia, Francesc; Cervera, Laura
The importance of developing new vaccine technologies towards versatile platforms that can cope with global virus outbreaks has been evidenced with the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Virus-like particles (VLPs) are a highly immunogenic, safe, and robust approach that can be used to base several vaccine candidates on. Particularly, HIV-1 Gag VLPs is a flexible system comprising a Gag core surrounded by a lipid bilayer that can be modified to present diverse types of membrane proteins or antigens against several diseases, like influenza, dengue, West Nile virus, or human papillomavirus, where it has been proven successful. The size distribution and structural characteristics of produced VLPs vary depending on the cell line used to produce them. In this study, we established an analytical method of characterization for the Gag protein core and clarified the current variability of Gag stoichiometry in HIV-1 VLPs depending on the cell-based production platform, directly determining the number of Gag molecules per VLP in each case. Three Gag peptides have been validated to quantify the number of monomers using parallel reaction monitoring, an accurate and fast, mass-spectrometry-based method that can be used to assess the quality of the produced Gag VLPs regardless of the cell line used. An average of 3617 ± 17 monomers per VLP was obtained for HEK293, substantially varying between platforms, including mammalian and insect cells. This offers a key advantage in quantification and quality control methods to characterize VLP production at a large scale to accelerate new recombinant vaccine production technologies.
Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs.
(ELSEVIER, 2021-02-09) Al-Mashhadi, Rozh H; Al-Mashhadi, Ahmed L; Nasr, Zahra P; Mortensen, Martin Bødtker; Lewis, Esmeralda A; Camafeita, Emilio; Ravlo, Kristian; Al-Mashhadi, Zheer; Kjær, Daniel W; Palmfeldt, Johan; Bie, Peter; Jensen, Jesper M; Nørgaard, Bjarne L; Falk, Erling; Vázquez, Jesús; Bentzon, Jacob F
The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9) Yucatan minipigs for >1 year. Caudal pressures remained normal. Under hypercholesterolemic conditions in PCSK9 transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.

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