14 results on '"Martin-Puig S"'
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2. Cardiac Metabolism.
- Author
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Martin-Puig S and Menendez-Montes I
- Subjects
- Humans, Animals, Heart, Cell Differentiation, Glycolysis, Oxidative Phosphorylation, Signal Transduction, Mitochondria, Heart metabolism, Energy Metabolism, Myocytes, Cardiac metabolism, Myocardium metabolism
- Abstract
The heart is composed of a heterogeneous mixture of cellular components perfectly intermingled and able to integrate common environmental signals to ensure proper cardiac function and performance. Metabolism defines a cell context-dependent signature that plays a critical role in survival, proliferation, or differentiation, being a recognized master piece of organ biology, modulating homeostasis, disease progression, and adaptation to tissue damage. The heart is a highly demanding organ, and adult cardiomyocytes require large amount of energy to fulfill adequate contractility. However, functioning under oxidative mitochondrial metabolism is accompanied with a concomitant elevation of harmful reactive oxygen species that indeed contributes to the progression of several cardiovascular pathologies and hampers the regenerative capacity of the mammalian heart. Cardiac metabolism is dynamic along embryonic development and substantially changes as cardiomyocytes mature and differentiate within the first days after birth. During early stages of cardiogenesis, anaerobic glycolysis is the main energetic program, while a progressive switch toward oxidative phosphorylation is a hallmark of myocardium differentiation. In response to cardiac injury, different signaling pathways participate in a metabolic rewiring to reactivate embryonic bioenergetic programs or the utilization of alternative substrates, reflecting the flexibility of heart metabolism and its central role in organ adaptation to external factors. Despite the well-established metabolic pattern of fetal, neonatal, and adult cardiomyocytes, our knowledge about the bioenergetics of other cardiac populations like endothelial cells, cardiac fibroblasts, or immune cells is limited. Considering the close intercellular communication and the influence of nonautonomous cues during heart development and after cardiac damage, it will be fundamental to better understand the metabolic programs in different cardiac cells in order to develop novel interventional opportunities based on metabolic rewiring to prevent heart failure and improve the limited regenerative capacity of the mammalian heart., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
- Published
- 2024
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3. Embryonic echocardiography for assessment of congenital and functional cardiac defects.
- Author
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Menendez-Montes I, Villalba-Orero M, Escobar B, and Martin-Puig S
- Subjects
- Animals, Female, Male, Mice, Pregnancy, Ultrasonography, Prenatal methods, Echocardiography methods, Embryo, Mammalian diagnostic imaging, Fetal Heart diagnostic imaging, Heart Defects, Congenital diagnostic imaging, Image Interpretation, Computer-Assisted methods
- Abstract
Cardiac function and morphology by mouse fetal echocardiography can be assessed by scanning the uterus extracted from the abdominal cavity (trans-uterine ultrasound) or the womb (trans-abdominal ultrasound). Advantages of trans-abdominal ultrasound include (1) non-invasive longitudinal analysis at different stages, reducing animal use; and (2) maintenance of natural environment, diminishing perturbations on functional parameters, which are more frequent in trans-uterine conditions. Here we describe both approaches, explaining how to identify congenital cardiac defects and defining the correlation between echocardiography findings and histological analysis. For complete details on the use and execution of this protocol, please refer to (Menendez-Montes et al., 2016) and (Menendez-Montes et al., 2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
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4. Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice.
- Author
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Menendez-Montes I, Escobar B, Gomez MJ, Albendea-Gomez T, Palacios B, Bonzon-Kulichenko E, Izquierdo-Garcia JL, Alonso AV, Ferrarini A, Jimenez-Borreguero LJ, Ruiz-Cabello J, Vázquez J, and Martin-Puig S
- Abstract
HIF1-alpha expression defines metabolic compartments in the developing heart, promoting glycolytic program in the compact myocardium and mitochondrial enrichment in the trabeculae. Nonetheless, its role in cardiogenesis is debated. To assess the importance of HIF1-alpha during heart development and the influence of glycolysis in ventricular chamber formation, herein we generated conditional knockout models of Hif1a in Nkx2.5 cardiac progenitors and cardiomyocytes. Deletion of Hif1a impairs embryonic glycolysis without influencing cardiomyocyte proliferation and results in increased mitochondrial number and transient activation of amino acid catabolism together with HIF2α and ATF4 upregulation by E12.5. Hif1a mutants display normal fatty acid oxidation program and do not show cardiac dysfunction in the adulthood. Our results demonstrate that cardiac HIF1 signaling and glycolysis are dispensable for mouse heart development and reveal the metabolic flexibility of the embryonic myocardium to consume amino acids, raising the potential use of alternative metabolic substrates as therapeutic interventions during ischemic events., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
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5. Metabolic Reprogramming in the Heart and Lung in a Murine Model of Pulmonary Arterial Hypertension.
- Author
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Izquierdo-Garcia JL, Arias T, Rojas Y, Garcia-Ruiz V, Santos A, Martin-Puig S, and Ruiz-Cabello J
- Abstract
A significant glycolytic shift in the cells of the pulmonary vasculature and right ventricle during pulmonary arterial hypertension (PAH) has been recently described. Due to the late complications and devastating course of any variant of this disease, there is a great need for animal models that reproduce potential metabolic reprograming of PAH. Our objective is to study, in situ , the metabolic reprogramming in the lung and the right ventricle of a mouse model of PAH by metabolomic profiling and molecular imaging. PAH was induced by chronic hypoxia exposure plus treatment with SU5416, a vascular endothelial growth factor receptor inhibitor. Lung and right ventricle samples were analyzed by magnetic resonance spectroscopy. In vivo energy metabolism was studied by positron emission tomography. Our results show that metabolomic profiling of lung samples clearly identifies significant alterations in glycolytic pathways. We also confirmed an upregulation of glutamine metabolism and alterations in lipid metabolism. Furthermore, we identified alterations in glycine and choline metabolism in lung tissues. Metabolic reprograming was also confirmed in right ventricle samples. Lactate and alanine, endpoints of glycolytic oxidation, were found to have increased concentrations in mice with PAH. Glutamine and taurine concentrations were correlated to specific ventricle hypertrophy features. We demonstrated that most of the metabolic features that characterize human PAH were detected in a hypoxia plus SU5416 mouse model and it may become a valuable tool to test new targeting treatments of this severe disease.
- Published
- 2018
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6. Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation.
- Author
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Menendez-Montes I, Escobar B, Palacios B, Gómez MJ, Izquierdo-Garcia JL, Flores L, Jiménez-Borreguero LJ, Aragones J, Ruiz-Cabello J, Torres M, and Martin-Puig S
- Subjects
- Animals, Cell Compartmentation, Down-Regulation genetics, Energy Metabolism, Female, Gene Deletion, Gene Expression Regulation, Developmental, Glycolysis, Heart Conduction System embryology, Heart Conduction System metabolism, Heart Failure embryology, Heart Failure metabolism, Mice, Inbred C57BL, Mitochondria metabolism, Mutation genetics, Myocardial Contraction, Oxidation-Reduction, Pregnancy, Stem Cells cytology, Stem Cells metabolism, Time Factors, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Myocardium metabolism, Organogenesis, Signal Transduction, Von Hippel-Lindau Tumor Suppressor Protein metabolism
- Abstract
While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1α regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1α and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1α hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for establishment of the cardiac conduction system. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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7. Novel perspectives on the PHD-HIF oxygen sensing pathway in cardioprotection mediated by IPC and RIPC.
- Author
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Martin-Puig S, Tello D, and Aragonés J
- Abstract
Reperfusion of ischemic cardiac tissue is the standard treatment for improving clinical outcome following myocardial infarction but is inevitably associated with ischemia-reperfusion injury (IRI). Ischemic myocardial injury can be alleviated by exposing the heart to brief episodes of sublethal ischemia-reperfusion prior to the ischemic insult, a phenomenon that has been termed ischemic preconditioning (IPC). Similarly, remote IPC (RIPC) is defined as transient episodes of ischemia at a distant site before a subsequent prolonged injury of the target organ. In this setting, adaptive responses to hypoxia/ischemia in peripheral tissues include the release of soluble factors that have the potential to protect cardiomyocytes remotely. Oxygen fluctuations is a hallmark of insufficient tissue perfusion and ischemic episodes. Emerging evidence indicates that prolyl hydroxylase oxygen sensors (PHDs) and hypoxia-inducible transcription factors (HIFs) are critical regulators of IPC and RIPC. In this review, we discuss recent findings concerning the role of the PHD-HIF axis in IPC and RIPC-mediated cardioprotection and examine molecular pathways and cell types that might be involved. We also appraise the therapeutic value of targeting the PHD-HIF axis to enhance cardiac tolerance against IRI.
- Published
- 2015
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8. Heart repair: from natural mechanisms of cardiomyocyte production to the design of new cardiac therapies.
- Author
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Martin-Puig S, Fuster V, and Torres M
- Subjects
- Animals, Cell Differentiation, Fetal Heart cytology, Fetal Heart embryology, Heart growth & development, Heart Diseases therapy, Homeostasis, Humans, Models, Cardiovascular, Myocytes, Cardiac physiology, Myocytes, Cardiac transplantation, Heart physiology, Myocytes, Cardiac cytology, Regeneration
- Abstract
Most organs in mammals, including the heart, show a certain level of plasticity and repair ability during gestation. This plasticity is, however, compromised for many organs in adulthood, resulting in the inability to repair organ injury, including heart damage produced by acute or chronic ischemic conditions. In contrast, lower vertebrates, such as fish or amphibians, retain a striking regenerative ability during their entire life, being able to repair heart injuries. There is a great interest in understanding both the mechanisms that allow heart plasticity during mammalian fetal life and those that permit adult cardiac regeneration in zebrafish. Here, we revise strategies for cardiomyocyte production during development and in response to injury and discuss differential regeneration ability of teleosts and mammals. Understanding these mechanisms may allow establishing alternative therapeutic approaches to cope with heart failure in humans., (© 2012 New York Academy of Sciences.)
- Published
- 2012
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9. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages.
- Author
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Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, and Chien KR
- Subjects
- Cell Differentiation, Cell Division, Cell Line, Coculture Techniques, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Endothelial Cells cytology, Fetus cytology, Fetus embryology, Heart embryology, Humans, LIM-Homeodomain Proteins, Muscle, Smooth cytology, Myocytes, Cardiac cytology, Transcription Factors, Wnt Proteins metabolism, Wnt3 Protein, Cell Lineage, Homeodomain Proteins metabolism, Multipotent Stem Cells cytology, Multipotent Stem Cells metabolism, Myocardium cytology
- Abstract
The generation and expansion of diverse cardiovascular cell lineages is a critical step during human cardiogenesis, with major implications for congenital heart disease. Unravelling the mechanisms for the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential. Recent studies in the mouse embryo have identified a multipotent cardiac progenitor that contributes to all of the major cell types in the murine heart. In contrast to murine development, human cardiogenesis has a much longer onset of heart cell lineage diversification and expansion, suggesting divergent pathways. Here we identify a diverse set of human fetal ISL1(+) cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle and endothelial cell lineages. Using two independent transgenic and gene-targeting approaches in human embryonic stem cell lines, we show that purified ISL1(+) primordial progenitors are capable of self-renewal and expansion before differentiation into the three major cell types in the heart. These results lay the foundation for the generation of human model systems for cardiovascular disease and novel approaches for human regenerative cardiovascular medicine.
- Published
- 2009
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10. Macrophage oxygen sensing modulates antigen presentation and phagocytic functions involving IFN-gamma production through the HIF-1 alpha transcription factor.
- Author
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Acosta-Iborra B, Elorza A, Olazabal IM, Martín-Cofreces NB, Martin-Puig S, Miró M, Calzada MJ, Aragonés J, Sánchez-Madrid F, and Landázuri MO
- Subjects
- Animals, Base Sequence, Cell Line, Cells, Cultured, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit deficiency, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Interferon-gamma genetics, Interferon-gamma metabolism, Macrophages metabolism, Macrophages, Peritoneal immunology, Macrophages, Peritoneal metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding immunology, Response Elements immunology, Antigen Presentation immunology, Hypoxia immunology, Hypoxia-Inducible Factor 1, alpha Subunit physiology, Interferon-gamma biosynthesis, Macrophages immunology, Oxygen metabolism, Phagocytosis immunology
- Abstract
Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-gamma and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-gamma increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-gamma induction was mediated through HIF-1alpha binding to its promoter on a new functional hypoxia response element. The requirement of HIF-alpha in the IFN-gamma induction was confirmed in RAW264.7 cells, where HIF-1alpha was knocked down, as well as in resident HIF-1alpha null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3epsilon, CD3zeta and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1alpha- and in IFN-gamma-silenced macrophages, indicating a link between HIF-1alpha and IFN-gamma in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1alpha-mediated increase in IFN-gamma levels.
- Published
- 2009
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11. Lives of a heart cell: tracing the origins of cardiac progenitors.
- Author
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Martin-Puig S, Wang Z, and Chien KR
- Subjects
- Humans, Regenerative Medicine, Cardiovascular Diseases physiopathology, Myocardium cytology, Stem Cells cytology
- Abstract
Heart cells are the unitary elements that define cardiac function and disease. The recent identification of distinct families of cardiovascular progenitor cells begins to build a foundation for our understanding of the developmental logic of human cardiovascular disease, and also points to new approaches to arrest and/or reverse its progression, a major goal of regenerative medicine. In this review, we highlight recent clarifications, revisions, and advances in our understanding of the many lives of a heart cell, with a primary focus on the emerging links between cardiogenesis and heart stem cell biology.
- Published
- 2008
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12. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway.
- Author
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Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, and Chien KR
- Subjects
- Animals, Cardiovascular System cytology, Cell Differentiation physiology, Cell Lineage, Embryo, Mammalian physiology, Female, Heart embryology, Heart physiology, Heart Defects, Congenital physiopathology, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, LIM-Homeodomain Proteins, Male, Mice, Signal Transduction, Stem Cells cytology, Transcription Factors, Wnt Proteins genetics, Wnt Proteins metabolism, beta Catenin genetics, beta Catenin metabolism, Cardiovascular System embryology, Homeodomain Proteins physiology, Stem Cells physiology, Wnt Proteins physiology, beta Catenin physiology
- Abstract
Isl1(+) cardiovascular progenitors and their downstream progeny play a pivotal role in cardiogenesis and lineage diversification of the heart. The mechanisms that control their renewal and differentiation are largely unknown. Herein, we show that the Wnt/beta-catenin pathway is a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of isl1(+) cardiovascular progenitors. This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal isl1(+) cardiovascular progenitors. In vivo activation of beta-catenin signaling in isl1(+) progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation, and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following beta-catenin deletion in isl1(+) precursors. Agents that manipulate Wnt signals can markedly expand isl1(+) progenitors from human neonatal hearts, a key advance toward the cloning of human isl1(+) heart progenitors.
- Published
- 2007
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13. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification.
- Author
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Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, and Chien KR
- Subjects
- Animals, Cell Culture Techniques, Cell Differentiation, Cell Lineage, Clone Cells, Heart embryology, Heterozygote, LIM-Homeodomain Proteins, Mice, Mice, Inbred Strains, Transcription Factors, Embryonic Stem Cells physiology, Endothelial Cells cytology, Homeodomain Proteins genetics, Multipotent Stem Cells physiology, Myocardium cytology, Myocytes, Cardiac cytology, Myocytes, Smooth Muscle cytology
- Abstract
Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1(+) precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1(+) cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1(+)/Nkx2.5(+)/flk1(+) defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1(+) cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.
- Published
- 2006
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14. The von Hippel Lindau/hypoxia-inducible factor (HIF) pathway regulates the transcription of the HIF-proline hydroxylase genes in response to low oxygen.
- Author
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del Peso L, Castellanos MC, Temes E, Martin-Puig S, Cuevas Y, Olmos G, and Landazuri MO
- Subjects
- Cell Line, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Von Hippel-Lindau Tumor Suppressor Protein, Gene Expression Regulation physiology, Oxygen metabolism, Procollagen-Proline Dioxygenase genetics, Transcription, Genetic physiology, Tumor Suppressor Proteins physiology, Ubiquitin-Protein Ligases physiology
- Abstract
Most of the genes induced by hypoxia are regulated by a family of transcription factors termed hypoxia-inducible factors (HIF). Under normoxic conditions, HIFalpha proteins are very unstable due to hydroxylation by a recently described family of proline hydroxylases termed EGL-Nine homologs (EGLN). Upon hydroxylation, HIFalpha is recognized by the product of the tumor suppressor vhl and targeted for proteosomal degradation. Since EGLNs require oxygen to catalyze HIF hydroxylation, this reaction does not efficiently occur under low oxygen tension. Thus, under hypoxia, HIFalpha escapes from degradation and transcribes target genes. The mRNA levels of two of the three EGLNs described to date are induced by hypoxia, suggesting that they might be novel HIF target genes; however, no proof for this hypothesis has been reported. Here we show that the induction of EGLN1 and -3 by hypoxia is found in a wide range of cell types. The basal levels of EGLN3 are always well below those of EGLN1 and EGLN2, and its induction by hypoxia is larger than that found for EGLN1. The inhibitor of transcription, actinomycin D, prevents the increase of EGLN3 mRNA induced by hypoxia, indicating that it is due to enhanced gene expression. Interestingly, EGLN1 and EGLN3 mRNAs were also triggered by EGLN inhibitors, suggesting the involvement of HIFalpha in the control of its transcription. In agreement with this possibility, pVHL-deficient cell lines, which present high HIF activity under normoxia, also showed dramatically increased normoxic levels of EGLN3. Moreover, the overexpression of an oxygen-insensitive mutant form of HIFalpha resulted in increased normoxic levels of EGLN3 mRNA. Finally, hypoxic induction of EGLNs was not observed in cells lacking functional HIFalpha.
- Published
- 2003
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