A5060277029- Nuclear Structure and Function
- RNA Research and Splicing
- Atherosclerosis and Cardiovascular Diseases
- Cancer-related Molecular Pathways
- Cell Adhesion Molecules Research
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- Adipokines, Inflammation, and Metabolic Diseases
- RNA modifications and cancer
- Angiogenesis and VEGF in Cancer
- Cancer, Hypoxia, and Metabolism
- Cancer, Lipids, and Metabolism
- Telomeres, Telomerase, and Senescence
- Genomics and Chromatin Dynamics
- Immune cells in cancer
- Blood disorders and treatments
- Genetics, Aging, and Longevity in Model Organisms
- PARP inhibition in cancer therapy
- Protein Tyrosine Phosphatases
- Immunodeficiency and Autoimmune Disorders
- Muscle Physiology and Disorders
- DNA Repair Mechanisms
- Metabolism and Genetic Disorders
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Coronary Interventions and Diagnostics
Centro de Investigación en Red en Enfermedades Cardiovasculares
2017-2025
Spanish National Centre for Cardiovascular Research
2015-2024
Centro de Investigación Biomédica en Red
2008-2024
Centre for Biomedical Network Research on Rare Diseases
2023
Instituto de Salud Carlos III
2007-2023
Centro Nacional de Investigaciones Científicas
2020
Universidad de Murcia
2020
Centro Regional de Hemodonación
2020
Hospital General Universitario Gregorio Marañón
2017
Lung Institute
2017
Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several these recurrent mutations, including those the gene encoding epigenetic modifier enzyme TET2, promote expansion mutant blood This clonal hematopoiesis correlates risk atherosclerotic cardiovascular disease. We studied effects Tet2-mutant cells atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr-/-) mice. found that partial bone marrow reconstitution TET2-deficient...
During terminal differentiation of skeletal myoblasts, cells fuse to form postmitotic multinucleated myotubes that cannot reinitiate DNA synthesis. Here we investigated the temporal relationships among these events during in vitro C2C12 myoblasts. Cells expressing myogenin, a marker for entry myoblasts into pathway, were detected first myogenesis, followed by appearance mononucleated both myogenin and cell cycle inhibitor p21. Although expression proteins was sustained mitogen-restimulated...
The terminal differentiation of C2C12 skeletal muscle cells involves the activation unique sets genes and an irreversible withdrawal from cell cycle. This process is associated with a decrease in cdk2 activity extracts. correlates diminished levels cyclin A marked induction p21 cyclin-dependent kinase (cdk) inhibitor. upregulation occurred at mRNA protein, formed complex kinases myotubes. Further, immunodepletion myotube extracts neutralized heat-stable inhibitory that was induced upon...
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates cryptic donor splice site and yields truncated form of prelamin A called progerin. Small amounts progerin are also produced during normal aging. Studies with mouse models HGPS have allowed recent development first therapeutic approaches for this disease. However, none these earlier works addressed aberrant pathogenic splicing observed patients because lack an appropriate model. Here, we...
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, role of HSC-intrinsic and -extrinsic mechanisms remains debated. Megakaryocytes promote quiescence neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change pathological/natural is unclear. Premature Hutchinson-Gilford progeria syndrome recapitulates physiological features, these arise from altered or niche unknown. Here, we show that BM...
A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death complications after myocardial infarction.In this phase 3, randomized, controlled clinical trial, we assigned patients infarction within previous 6 months polypill-based strategy or usual care. The treatment consisted aspirin (100 mg), ramipril (2.5, 5, 10...
Even when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) associated with subclinical and vascular inflammation regardless LDL-C. This study sought to assess the association between serum TG early in apparently healthy individuals. An observational, longitudinal, prospective cohort study, including 3,754 middle-aged individuals low moderate cardiovascular from PESA...
Abstract Aims Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim this article to assess the association subclinical atherosclerosis with accelerated epigenetic investigate underlying mechanisms mediating association. Methods results Whole blood methylomics, transcriptomics, plasma proteomics were obtained for 391 participants Progression Early Subclinical Atherosclerosis study. was calculated from methylomics data each participant. Its divergence...
Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal dynamics (ie, progression or regression) of human subclinical atherosclerosis and their determinants scarce. This study sought to investigate within cohort middle-aged, asymptomatic individuals by using multiterritorial 3-dimensional vascular ultrasound (3DVUS) imaging. A total 3,471 participants from PESA (Progression Early Subclinical Atherosclerosis) (baseline age 40-55 years;...
Background Clinical studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of in-stent restenosis. However, pathological data regarding this issue are limited. Specifically, direct evidence proliferative activity in tissues excised from stenotic stents has not been previously reported. Methods and Results Tissue specimens were retrieved by directional atherectomy 10 patients whom restenosis complicated percutaneous revascularization peripheral artery...
The myocyte enhancer-binding factor 2 (MEF2) site is an essential element of many muscle-specific enhancers and promoters that binds nuclear proteins from muscle brain. Recently, we have cloned a family MEF2 transcription factors produced by two genes that, at the mRNA level, are broadly expressed produce tissue-specific isoforms posttranscriptional processes (Y.-T. Yu, R. E. Breitbart, L. B. Smoot, Y. Lee, V. Mahdavi, Nadal-Ginard, Genes Dev. 6:1783-1798, 1992). Here, report isolation...
AP-1 (Activating Protein 1) transcription factor activity is tightly regulated at multiple levels, including dimer formation (i.e., Fos/Jun). Here we show that the intermediate filament protein lamin A/C suppresses function through direct interaction with c-Fos, and both proteins can interact colocalize nuclear envelope (NE) in mammalian cells. Perinuclear localization of c-Fos absent Lmna -null cells but be restored by A overexpression. In vitro, preincubation prior to addition c-Jun...
Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to death, predominantly myocardial infarction or stroke. The goal this study was investigate mechanisms cause in HGPS.We performed expression functional studies wild-type mice knock-in Lmna(G609G/+) expressing progerin, which mimic the main clinical manifestations HGPS. showed aortic...
Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal hyperplasia during atherosclerosis and restenosis, but the endogenous cell cycle regulatory factors underlying VSMC growth in response arterial injury are not well understood. In present study, we report that downregulation cyclin-dependent kinase 2 (cdk2) activity serum-deprived VSMCs was associated with formation complexes between cdk2 its inhibitory protein p27(KIP1) (p27). Ectopic overexpression p27...
Sequestration of c-Fos at the nuclear envelope (NE) through interaction with A-type lamins suppresses AP-1–dependent transcription. We show here that accumulation within extraction-resistant fraction (ERNF) and its lamin A are reduced enhanced by gain-of loss-of ERK1/2 activity, respectively. Moreover, hindering ERK1/2-dependent phosphorylation attenuates release from ERNF induced serum promotes A. Accordingly, stimulation rapidly releases preexisting NE via phosphorylation, leading to a...
Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, part, because lack appropriate animal models.We generated atherosclerosis-prone model by crossing apolipoprotein...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using transcriptomic approach,...