446 research outputs found
Acute oxygen sensing by vascular smooth muscle cells
No full text© 2023 Moreno-Domínguez, Colinas, Smani, Ureña and López-Barneo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.An adequate supply of oxygen (O2) is essential for most life forms on earth, making the delivery of appropriate levels of O2 to tissues a fundamental physiological challenge. When O2 levels in the alveoli and/or blood are low, compensatory adaptive reflexes are produced that increase the uptake of O2 and its distribution to tissues within a few seconds. This paper analyzes the most important acute vasomotor responses to lack of O2 (hypoxia): hypoxic pulmonary vasoconstriction (HPV) and hypoxic vasodilation (HVD). HPV affects distal pulmonary (resistance) arteries, with its homeostatic role being to divert blood to well ventilated alveoli to thereby optimize the ventilation/perfusion ratio. HVD is produced in most systemic arteries, in particular in the skeletal muscle, coronary, and cerebral circulations, to increase blood supply to poorly oxygenated tissues. Although vasomotor responses to hypoxia are modulated by endothelial factors and autonomic innervation, it is well established that arterial smooth muscle cells contain an acute O2 sensing system capable of detecting changes in O2 tension and to signal membrane ion channels, which in turn regulate cytosolic Ca2+ levels and myocyte contraction. Here, we summarize current knowledge on the nature of O2 sensing and signaling systems underlying acute vasomotor responses to hypoxia. We also discuss similarities and differences existing in O2 sensors and effectors in the various arterial territories.This research was supported by the Andalusian Government (FEDER Andalucía 2014–2020, 2018 Call, US-1255654), the Spanish Ministries of Science and Innovation and Health (Grants SAF 2016-74990-R and PID 2019-106410RB-I00 funded by MCIN/AEI/10.13039/501100011033), and the European Research Council (ERC Advanced Grant PRJ201502629).Peer reviewe
Reduced risk of pancreatic cancer associated with asthma and nasal allergies
No full textThe work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (PI11/01542, PI0902102, PI12/01635, PI12/00815); Red Temática de Investigación Cooperativa en Cáncer, Spain (RD12/ 0036/0034, RD12/0036/0050, #RD12/0036/0073); European Cooperation in science and Technology - COST Action BM1204: EUPancreas. Acción Especial de Genómica, Spain (GEN2001-4748-c05-03); EU-6FP Integrated Project (018771-MOLDIAG-PACA), EU-FP7-HEALTH (#259737-CANCERALIA, 256974-EPC-TM-Net), Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (SLL20130022), Sweden.Gomez-Rubio, P., Zock, J.-P., Rava, M., Marquez, M., Sharp, L., Hidalgo, M., Carrato, A., Ilzarbe, L., Michalski, C., Molero, X., Farré, A., Perea, J., Greenhalf, W., O'Rorke, M., Tardón, A., Gress, T., Barberà, V., Crnogorac-Jurcevic, T., Domínguez-Munõz, E., Munõz-Bellvís, L., Alvarez-Urturi, C., Balcells, J., Barneo, L., Costello, E., Guillén-Ponce, C., Kleeff, J., Kong, B., Lawlor, R., Löhr, M., Mora, J., Murray, L., O'Driscoll, D., Pelaéz, P., Poves, I., Scarpa, A., Real, F.X., Malats, N
Fifteen Years of Baeza's Workshops : Current Trends in Biomedicine (2004-2019) = 15 Aniversario Encuentros Internacionales en Biomedicina
No full text497 p."The Current trends in Biomedicine workshops" were created in 2004. These workshops are spaces for dialogue and reflection on the latest advances on topics such as the nervous system, genetic transcription or the role of bacteria in human health. Approximately 1,000 people have participated in these workshops, in which the UNIA contributes all of its logistic capacity and has made a million-euro investment. This publication commemorates the 15 th anniversary of the project. It is the quality of the proposals received, rather than the time of its existence, that best indicates that the consolidation phase has been reached. Still relatively new, the current objective is to improve the project’s notoriety and the intensity of the debates. This will ensure that these seminars are essential events on international scientific calendars. Biomedicine Advisory Board: José López-Barneo; Aurora Bueno Cavanillas; Josep Casadesús; José Luis Gómez-Skarmeta; Diego Rodríguez-Puyol // En 2004 se ponen en marcha los workshops "Current Trends in Biomedicine". Un espacio destinado al diálogo y la reflexión en torno a los últimos avances sobre el sistema nervioso, la transcripción genética o la implicación de las bacterias en la salud humana, entre otras materias. Cerca de 1.000 personas han participado en esta cita, donde la UNIA ha puesto toda su capacidad logística y una inversión que, hasta la fecha, suma el millón de euros. Esta publicación conmemora el 15 aniversario de este proyecto. Pero no es el tiempo, sino la calidad de las propuestas recibidas, el mejor indicador de que se ha alcanzado una fase de consolidación. Conscientes de su juventud, el objetivo ahora es incidir en mejorar la notoriedad y la intensidad de los debates. Haciendo de estos seminarios una visita cada vez más imprescindible en el calendario científico internacional
Neurotransmitter Modulation of Carotid Body Germinal Niche
No full textThe carotid body (CB), a neural-crest-derived organ and the main arterial chemoreceptor in mammals, is composed of clusters of cells called glomeruli. Each glomerulus contains neuron-like, O2-sensing glomus cells, which are innervated by sensory fibers of the petrosal ganglion and are located in close contact with a dense network of fenestrated capillaries. In response to hypoxia, glomus cells release transmitters to activate afferent fibers impinging on the respiratory and autonomic centers to induce hyperventilation and sympathetic activation. Glomus cells are embraced by interdigitating processes of sustentacular, glia-like, type II cells. The CB has an extraordinary structural plasticity, unusual for a neural tissue, as it can grow several folds its size in subjects exposed to sustained hypoxia (as for example in high altitude dwellers or in patients with cardiopulmonary diseases). CB growth in hypoxia is mainly due to the generation of new glomeruli and blood vessels. In recent years it has been shown that the adult CB contains a collection of quiescent multipotent stem cells, as well as immature progenitors committed to the neurogenic or the angiogenic lineages. Herein, we review the main properties of the different cell types in the CB germinal niche. We also summarize experimental data suggesting that O2-sensitive glomus cells are the master regulators of CB plasticity. Upon exposure to hypoxia, neurotransmitters and neuromodulators released by glomus cells act as paracrine signals that induce proliferation and differentiation of multipotent stem cells and progenitors, thus causing CB hypertrophy and an increased sensory output. Pharmacological modulation of glomus cell activity might constitute a useful clinical tool to fight pathologies associated with exaggerated sympathetic outflow due to CB overactivationMinisterio de Ciencia e Innovación de España (SAF2012-39343 y SAF2016-74990-R a JL-B., Y SAF2016-80412-P y PID2019-110817R a RP)Consejo Europeo de Investigación (ERC -ADGPRJ201502629 a JL-B. Y ERC-STGCBSCS a RP
Oxygen sensing by human recombinant tandem-P domain potassium channels
No full textOxygen sensing in many tissues is crucially dependent upon hypoxia-evoked suppression of K+ channel activity (Kemp et al. 2003; Lopez-Barneo et al. 2001; Peers, 1997; Patel and Honore, 2001; Peers & Kemp, 2001). This is particularly true of the prospective airway O2 sensor, the neuroepithelial body of the lung (Youngson et al. 1993; Cutz and Jackson, 1999), their immortalised cellular counterpart (HI46 cells - O’Kelly et al. 1998; O’Kelly et al. 2000b; O’Kelly et al. 2000a; Hartness et al. 2001; O’Kelly et al. 1999; Kemp et al. 2003) and the arterial O2 sensor, the carotid body (Lopez-Barneo et al. 1988; Peers, 1990; Buckler, 1997). In addition, the K+ channels almost certainly contribute to hypoxic vasoconstriction of the pulmonary vasculature (Post et al. 1992; Weir & Archer, 1995; Osipenko et al. 2000 Coppock et al. 2001;) although the full extent and nature of their involvement is still somewhat controversial (Ward & Aaronson, 1999). Although each tissue and model system expresses a cell-specific gamut of K+ channels, central to O2 sensory transduction in several is hypoxic inhibition of members of the gene family encoding tandem P- domain (K2p) K+ channels. Such background K+ channels contribute to the maintenance of resting membrane potential in cells where they are expressed and ascription of specific K2p channels to cellular hypoxic responses have been shown directly in the airway chemosensing model H146 cells (Hartness et al. 2001) - TASK3) and inferred in carotid body glomus cells (Buckler et al. 2000) - TASK1) and arteriolar smooth muscle of the pulmonary circulation(Gurney et al. 2002) - TASK1 or TASK3). The current exception to this potentially unifying theme in acute O2 sensing is the native neuroepithelial body, where involvement of K2p channels has not been robustly investigated other than by demonstration immunohistochemically of the TASK2 protein (Kemp et al. 2003)
Molecular Mechanisms of Acute Oxygen Sensing by Arterial Chemoreceptor Cells. Role of Hif2α
No full textCarotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O2 homeostasis. Glomus cells are prototypical peripheral O2 sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O2 sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca2+ influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O2 tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. A mitochondrial-to-membrane signaling model of acute O2 sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.This research was supported by the Spanish Ministries of Science and Innovation and Health (SAF2012-39343 and SAF2016-74990-R) and the European Research Council (ERC-ADGPRJ201502629)
Author Correction: Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice
No full textAging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.Funding for this project was provided by the following NIH grants: NIH2PO1HL071643-11A1, NIH1R35CA197532-01 to N.S.C.; NIH1PO1AG049665-01 to G.R.S.B and N.S.C.; NIH/NCI T32CA09560 to G.S.M.; NIH P01 AG049665, P01 HL071643, P01 HL154998 to K.R.NIH/NCI T32CA09560 to G.S.M.; NHLBI F32HL136111 to P.A.R.; P.A.R. was supported by an American Thoracic Society/Boehringer Ingelheim Partner. We thank the following core facilities at Northwestern: Pulmonary NextGen Sequencing Core, RHLCCC Metabolomics Core, RHLCCC Flow Cytometry Core Facility. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the RHLCC.Peer reviewe
Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport
No full text[Peer review]
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/1873-3468.70017.Carotid body glomus cells are essential for stimulating breathing in response to hypoxia. They contain specialized mitochondria in which hypoxia induces the accumulation of NADH and H2O2 that modulate membrane ion channel activity. We investigated whether hypoxia induces reverse electron transport (RET) at mitochondrial complex I (MCI). We studied glomus cells from mice with a mutation in ND6, a core protein of MCI, which maintain normal MCI NADH dehydrogenase activity but cannot catalyze RET. The ND6 mutation increases the propensity of MCI to deactivate, and glomus cells with deactivated MCI are insensitive to acute hypoxia. These findings further indicate that MCI function is necessary for glomus cell responsiveness to hypoxia, although MCI RET does not seem to be required for this process.We thank the generous supply of ND6 P25L mice from Dr Douglas C Wallace's laboratory (Children's Hospital of Philadelphia, Philadelphia, USA). This research was supported by the Andalusian Government (FEDER Andalucía 2014–2020, 2018 Call, US-1255654, PO-S and LG), the Spanish Ministries of Science and Innovation and Health (Grants SAF2016-74990-R, PID2019-106410RB-I00, and PID2023-146862OB-100 funded by MCIN/AEI/10.13039/501100011033, JL-B, LG and PO-S), and the European Research Council (ERC Advanced Grant PRJ201502629, JL-B). MT-L received a predoctoral fellowship (FPI program) from the Spanish Government.Peer reviewe
Lactate sensing mechanisms in arterial chemoreceptor cells
No full textLactate levels in blood change during hypoxia or exercise, however whether this variable is sensed to evoke adaptive responses is unknown. Here the authors show that oxygen-sensing carotid body cells stimulated by hypoxia are also activated by lactate to potentiate a compensatory ventilatory response
Author Correction: Disruption of mitochondrial complex I induces progressive parkinsonism
No full textIn the version of this article initially published, the two bottom-left panels in Extended Data Fig. 8b duplicated the top-left and bottom-right panels of Fig. 4d presenting open field traces in mice. The panels have now been replaced with new images. The errors have been corrected in the online version of the article.Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease1. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm.Electron microscopy tissue processing and imaging was performed at the Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This study was supported by grants from the Michael J. Fox Foundation (to D.J.S.), the JPB Foundation (to D.J.S.), the IDP Foundation (to D.J.S.), the Flanagan Fellowship (to P.G.-R.) and the European Research Council ERC Advanced Grant PRJ201502629 (to J.L.-B.).Peer reviewe
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