Spanish National Cardiovascular Research Center

Madrid, Spain

Spanish National Cardiovascular Research Center

Madrid, Spain
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Roszer T.,Spanish National Cardiovascular Research Center | Roszer T.,Hungarian Academy of Sciences | Jozsa T.,Karolinska University Hospital | Kiss-Toth E.D.,Hungarian Academy of Sciences | And 2 more authors.
Cell and Tissue Research | Year: 2014

Increased fragility fracture risk with improper healing is a frequent and severe complication of insulin resistance (IR). The mechanisms impairing bone health in IR are still not fully appreciated, which gives importance to studies on bone pathologies in animal models of diabetes. Mice deficient in leptin signaling are widely used models of IR and its comorbidities. Leptin was first recognized as a hormone, regulating appetite and energy balance; however, recent studies have expanded its role showing that leptin is a link between insulin-dependent metabolism and bone homeostasis. In the light of these findings, it is intriguing to consider the role of leptin resistance in bone regeneration. In this study, we show that obese diabetic mice lacking leptin receptor (db/db) are deficient in postnatal regenerative osteogenesis. We apply an ectopic osteogenesis and a fracture healing model, both showing that db/db mice display compromised bone acquisition and regeneration capacity. The underlying mechanisms include delayed periosteal mesenchymatic osteogenesis, premature apoptosis of the cartilage callus and impaired microvascular invasion of the healing tissue. Our study supports the use of the db/db mouse as a model of IR associated bone-healing deficits and can aid further studies of mesenchymatic cell homing and differentiation, microvascular invasion, cartilage to bone transition and callus remodeling in diabetic fracture healing. © 2013 Springer-Verlag Berlin Heidelberg.


PubMed | Howard Hughes Medical Institute, Microscopy Unit, Spanish National Cardiovascular Research Center and CIEMAT
Type: | Journal: Stem cell research & therapy | Year: 2015

The mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life. Although many cardiac stem cell populations have been studied, the natural source for homeostatic repair has not yet been defined. The Polycomb protein BMI1 is the most representative marker of mouse adult stem cell systems. We have evaluated the relevance and role of cardiac Bmi1 (+) cells in cardiac physiological homeostasis.Bmi1 (CreER/+);Rosa26 (YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1 (+) cells. These cells and their progeny were tracked by FACS, immunofluorescence and RT-qPCR techniques from 5 days to 1 year.FACS analysis of non-cardiomyocyte compartment from TM-induced Bmi1-YFP mice showed a Bmi1 (+)-expressing cardiac progenitor cell (Bmi1-CPC: B-CPC) population, SCA-1 antigen-positive (95.90.4 %) that expresses some stemness-associated genes. B-CPC were also able to differentiate in vitro to the three main cardiac lineages. Pulse-chase analysis showed that B-CPC remained quite stable for extended periods (up to 1 year), which suggests that this Bmi1 (+) population contains cardiac progenitors with substantial self-maintenance potential. Specific immunostaining of Bmi1-YFP hearts serial sections 5 days post-TM induction indicated broad distribution of B-CPC, which were detected in variably sized clusters, although no YFP(+) cardiomyocytes (CM) were detected at this time. Between 2 to 12 months after TM induction, YFP(+) CM were clearly identified (30.6 % to 6.71.3 %) by immunohistochemistry of serial sections and by flow cytometry of total freshly isolated CM. B-CPC also contributed to endothelial and smooth muscle (SM) lineages in vivo.High Bmi1 expression identifies a non-cardiomyocyte resident cardiac population (B-CPC) that contributes to the main lineages of the heart in vitro and in vivo.


Tarin C.,Vascular Research Laboratory | Fernandez-Laso V.,Vascular Research Laboratory | Sastre C.,Vascular Research Laboratory | Madrigal-Matute J.,Vascular Research Laboratory | And 6 more authors.
Journal of the American Heart Association | Year: 2014

Background-Abdominal aortic aneurysm (AAA) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown. Methods and Results-Experimental AAA with aortic elastase perfusion in mice was induced in wild-type (WT), TWEAK deficient (TWEAK KO), or Fn14-deficient (Fn14 KO) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD3+ T cells, neutrophils, CD31+ microvessels, CCL2 and CCL5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells (VSMC) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL5 secretion and MMP-9 activation in both VSMC and bone marrow-derived macrophages, and decrease VSMC viability, effects dependent on Fn14. Conclusions-TWEAK/Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix-degrading protease expression, and vascular remodeling. Blocking TWEAK/Fn14 interaction could be a new target for the treatment of AAA. © 2014 The Authors.


Gonzalez-Navarro H.,Institute Biomedicina Of Valencia Ibv | Abu Nabah Y.N.,Institute Biomedicina Of Valencia Ibv | Vinue A.,Institute Biomedicina Of Valencia Ibv | Andres-Manzano M.J.,Spanish National Cardiovascular Research Center | And 4 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: The goal of this study was to investigate the role in atherosclerosis of the tumor suppressor protein ARF (human p14ARF, mouse p19ARF) encoded by the CDKN2A gene. Background: Atherosclerosis is characterized by excessive proliferation and apoptosis, 2 cellular processes regulated by CDKN2A. Although recent genome-wide association studies have linked atherosclerotic diseases to a genomic region in human chromosome 9p21 near the CDKN2A locus, the mechanisms underlying this gene-disease association remain undefined, and no causal link has been established between CDKN2A and atherosclerosis. Methods: Atherosclerosis-prone apolipoprotein E (apoE)-null and doubly deficient apoE-p19ARF mice were fed an atherogenic diet and sacrificed to quantify atherosclerosis burden in whole-mounted aortas and in aortic cross-sections. Proliferation and apoptosis were investigated in atherosclerotic lesions and in primary cultures of macrophages and vascular smooth muscle cells obtained from both groups of mice. Results: Genetic disruption of p19ARF in apoE-null mice augments aortic atherosclerosis without affecting body weight, plasma lipoproteins, or plaque's proliferative activity. Notably, p19ARF deficiency significantly attenuates apoptosis both in atherosclerotic lesions and in cultured macrophages and vascular smooth muscle cells, 2 major cellular constituents of atheromatous plaques. Conclusions: Our findings establish a direct link between p19ARF, plaque apoptosis, and atherosclerosis, and suggest that human genetic variants associated to diminished CDKN2A expression may accelerate atherosclerosis by limiting plaque apoptosis. © 2010 American College of Cardiology Foundation.


PubMed | California Stem Cell, Compared Pathology Unit, Flow Cytometry Unit, Spanish National Cardiovascular Research Center and 2 more.
Type: | Journal: Nature communications | Year: 2015

Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These dormant origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality.


Fuster J.J.,Institute Biomedicina Of Valencia Csic | Fernandez P.,Institute Biomedicina Of Valencia Csic | Gonzalez-Navarro H.,Institute Biomedicina Of Valencia Csic | Silvestre C.,Institute Biomedicina Of Valencia Csic | And 4 more authors.
Cardiovascular Research | Year: 2010

Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors. The purpose of this review is to summarize current knowledge about the role of these cell cycle regulators in the development of native and graft atherosclerosis that has arisen from animal studies, histological examination of specimens from human patients, and genetic studies. © The Author 2009. For permissions please.


Rszer T.,Debrecen University | Rszer T.,Spanish National Cardiovascular Research Center | Banfalvi G.,Debrecen University
Peptides | Year: 2012

Members of the FMRFamide-related peptide (FaRP) family are neurotransmitters, hormone-like substances and tumor suppressor peptides. In mammals, FaRPs are considered as anti-opiate peptides due to their ability to inhibit opioid signaling. Some FaRPs are asserted to attenuate opiate tolerance. A recently developed chimeric FaRP (Met-enkephalin-FMRFa) mimics the analgesic effects of opiates without the development of opiate-dependence, displaying a future therapeutical potential in pain reduction. In this review we support the notion, that opiates and representative members of the FaRP family show overlapping effects on apoptosis. Binding of FaRPs to opioid receptors or to their own receptors (G-protein linked membrane receptors and acid-sensing ion channels) evokes or suppresses cell death, in a cell- and receptor-type manner. With the dramatically increasing incidence of opiate abuse and addiction, understanding of opioid-induced cell death, and in this context FaRPs will deserve growing attention. © 2011 Elsevier Inc. All rights reserved.


Rszer T.,Spanish National Cardiovascular Research Center | Ricote M.,Spanish National Cardiovascular Research Center
PPAR Research | Year: 2010

Recent research has revealed roles for the peroxisome proliferator activated receptor (PPAR) family of transcription factors in blood pressure regulation, expanding the possible therapeutic use of PPAR ligands. PPAR and PPAR modulate the renin-angiotensin-aldosterone system (RAAS), a major regulator of systemic blood pressure and interstitial fluid volume by transcriptional control of renin, angiotensinogen, angiotensin converting enzyme (ACE) and angiotensin II receptor 1 (AT-R1). Blockade of RAAS is an important therapeutic target in hypertension management and attenuates microvascular damage, glomerular inflammation and left ventricular hypertrophy in hypertensive patients and also show antidiabetic effects. The mechanisms underlying the benefits of RAAS inhibition appear to involve PPAR -regulated pathways. This review summarizes current knowledge on the role of PPARs in the transcriptional control of the RAAS and the possible use of PPAR ligands in the treatment of RAAS dependent hypertension. © 2010 T. Röszer and M. Ricote.


Roszer T.,Spanish National Cardiovascular Research Center
The Biology of Subcellular Nitric Oxide | Year: 2012

This book fills in a gap in the NO literature. Recent progress in the field of NO-biology shows that NO is generated within distinct cell compartments, including specific plasma membrane regions, mitochondria, chloroplasts, peroxisomes, the Golgi-complex and intracellular membrane systems. NO synthesis plays specific roles in these compartments and, in turn, cell organelles also control intracellular NO levels. This monograph focuses on the roles played by the subcellular NO-signaling microdomains in the prokaryote-, fungus-, plant- and animal cells and shows how NO behaves as an intracellular signal in distinct cellular environments. This monograph also provides a summary of our knowledge on how NO synthesis came through evolution to be associated with organelles and subcellular compartments. Promotes the novel ideas that some functions of NO and its associations with subcellular units have been conserved during the evolution of the cell. A special chapter is dedicated to the biomedical relevance of subcellular NO synthesis, and this chapter also discusses the evidence that altered compartmentalization of NO-producing enzymes causes disease. © Springer Science+Business Media Dordrecht 2013. All rights reserved.


PubMed | Spanish National Cardiovascular Research Center
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2015

We present here a procedure that allows real-time high-resolution multichannel imaging of early atherosclerotic lesions of live mice, by dramatically reducing the respiratory and pulsatile movements of the athero-susceptible carotid artery, without significantly altering blood flow dynamics. This surgical preparation can be combined with the use of various fluorescent probes and reporter mice to simultaneously visualize the dynamics of inflammatory leukocytes, platelets, or even subcellular structures. Stabilization of the tissue renders it suitable for two-photon laser scanning microscopic imaging and allows tracking the behavior of inflammatory cells in three dimensions.

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