O P Ottersen

University of Oslo, Kristiania (historical), Oslo, Norway

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Publications (389)1851.31 Total impact

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    ABSTRACT: The brain-blood interface holds the key to our understanding of how cerebral blood flow is regulated and how water and solutes are exchanged between blood and brain. The highly specialized astrocytic membranes that enwrap brain microvessels are salient constituents of the brain-blood interface. These endfoot membranes contain a distinct set of molecules that is anchored to the subendothelial basal lamina forming an endfoot-basal lamina junctional complex. Here we explore the mechanisms underpinning the formation of this complex. By use of a tailor made model system we show that endothelial cells promote AQP4 accumulation by exerting an inductive effect through extracellular matrix components such as agrin, as well as through a direct mechanical interaction with the endfoot processes. Through the compounds they secrete, the endothelial cells also increase AQP4 expression. The present data suggest that the highly specialized gliovascular interface is established through inductive processes that include both chemical and mechanical factors. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 06/2015; DOI:10.1002/glia.22878 · 6.03 Impact Factor
  • D McNeill · O P Ottersen
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    ABSTRACT: In this article, we address a central theme that was discussed at the Durham Health Summit: how can politics be brought back into global health governance and figure much more prominently in discussions around policy? We begin by briefly summarizing the report of the Lancet - University of Oslo Commission on Global Governance for Health: 'The Political Origins of Health Inequity' Ottersen et al. In order to provide compelling evidence of the central argument, the Commission selected seven case studies relating to, inter alia, economic and fiscal policy, food security, and foreign trade and investment agreements. Based on an analysis of these studies, the report concludes that the problems identified are often due to political choices: an unwillingness to change the global system of governance. This raises the question: what is the most effective way that a report of this kind can be used to motivate policy-makers, and the public at large, to demand change? What kind of moral or rational argument is most likely to lead to action? In this paper we assess the merits of various alternative perspectives: health as an investment; health as a global public good; health and human security; health and human development; health as a human right; health and global justice. We conclude that what is required in order to motivate change is a more explicitly political and moral perspective - favouring the later rather than the earlier alternatives just listed. Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
    Public health 06/2015; DOI:10.1016/j.puhe.2015.05.001 · 1.48 Impact Factor
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    ABSTRACT: Astrocytic endfeet are specialized cell compartments whose important homeostatic roles depend on their enrichment of water and ion channels anchored by the dystrophin associated protein complex (DAPC). This protein complex is known to disassemble in patients with mesial temporal lobe epilepsy and in the latent phase of experimental epilepsies. The mechanistic underpinning of this disassembly is an obvious target of future therapies, but remains unresolved. Here we show in a kainate model of temporal lobe epilepsy that astrocytic endfeet display an enhanced stimulation-evoked Ca(2+) signal that outlast the Ca(2+) signal in the cell bodies. While the amplitude of this Ca(2+) signal is reduced following group I/II metabotropic receptor (mGluR) blockade, the duration is sustained. Based on previous studies it has been hypothesized that the molecular disassembly in astrocytic endfeet is caused by dystrophin cleavage mediated by Ca(2+) dependent proteases. Using a newly developed genetically encoded Ca(2+) sensor, the present study bolsters this hypothesis by demonstrating long-lasting, enhanced stimulation-evoked Ca(2+) signals in astrocytic endfeet.
    Frontiers in Cellular Neuroscience 02/2015; 9:49. DOI:10.3389/fncel.2015.00049 · 4.18 Impact Factor
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    ABSTRACT: Brain ependymal cells, which form an epithelial layer covering the cerebral ventricles, have been shown to play a role in the regulation of cerebrospinal and interstitial fluids. The machinery underlying this, however, remains largely unknown. Here, we report the specific localization of an inwardly rectifying K(+) channel, Kir4.1, on the ependymal cell membrane suggesting involvement of the channel in this function. Immunohistochemical study with confocal microscopy identified Kir4.1 labeling on the lateral but not apical membrane of ependymal cells. Ultrastructural analysis revealed that Kir4.1-immunogold particles were specifically localized and clustered on adjacent membranes at puncta adherens type junctions, whereas an aquaporin water channel, AQP4, that was also detected on the lateral membrane only occurred at components other than adherens junctions. Therefore, in ependymal cells, Kir4.1 and AQP4 are partitioned into distinct membrane compartments that might respectively transport either K(+) or water. Kir4.1 was also expressed in a specialized form of ependymal cell, namely the tanycyte, being abundant in tanycyte processes wrapping neuropils and blood vessels. These specific localizations suggest that Kir4.1 mediates intercellular K(+) exchange between ependymal cells and also K(+)-buffering transport via tanycytes that can interconnect neurons and vessels/ventricles. We propose that ependymal cells and tanycytes differentially operate Kir4.1 and AQP4 actively to control the property of fluids at local areas in the brain.
    Cell and Tissue Research 11/2014; 359(2). DOI:10.1007/s00441-014-2030-6 · 3.33 Impact Factor
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    ABSTRACT: Astrocytes are highly polarised cells with processes that ensheath microvessels, cover the brain surface, and abut synapses. The endfoot membrane domains facing microvessels and pia are enriched with aquaporin-4 water channels (AQP4) and other members of the dystrophin associated protein complex (DAPC). Several lines of evidence show that loss of astrocyte polarization, defined by the loss of proteins that are normally enriched in astrocyte endfeet, is a common denominator of several neurological diseases such as mesial temporal lobe epilepsy, Alzheimer's disease, and stroke. Little is known about the mechanisms responsible for inducing astrocyte polarization in vivo. Here we introduce the term endfoot-basal lamina junctional complex (EBJC) to denote the proteins that consolidate and characterize the gliovascular interface. The present study was initiated in order to resolve the developmental profile of the EBJC in mouse brain. We show that the EBJC is established after the first week postnatally. Through a combination of methodological approaches, including light microscopic and high resolution immunogold cytochemistry, quantitative RT-PCR, and Western blotting, we demonstrate that the different members of this complex exhibit distinct ontogenic profiles--with the extracellular matrix (ECM) proteins laminin and agrin appearing earlier than the other members of the complex. Specifically, while laminin and agrin expression peak at P7, quantitative immunoblot analyses indicate that AQP4, α-syntrophin, and the inwardly rectifying K(+) channel Kir4.1 expression increases towards adulthood. Our findings are consistent with ECM having an instructive role in establishing astrocyte polarization in postnatal development and emphasize the need to explore the involvement of ECM in neurological disease.
    Brain Structure and Function 04/2014; 220(4). DOI:10.1007/s00429-014-0775-z · 4.57 Impact Factor
  • The Lancet 04/2014; 383(9926):1380-1. DOI:10.1016/S0140-6736(14)60676-0 · 45.22 Impact Factor
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    ABSTRACT: The coupling between the water channel aquaporin-4 (AQP4) and K(+) transport has attracted much interest. In this study, we assessed the effect of Aqp4 deletion on activity-induced [K(+)]o changes in acute slices from hippocampus and corpus callosum of adult mice. We show that Aqp4 deletion has a layer-specific effect on [K(+)]o that precisely mirrors the known effect on extracellular volume dynamics. In CA1, the peak [K(+)]o in stratum radiatum during 20 Hz stimulation of Schaffer collateral/commissural fibers was significantly higher in Aqp4 (-/-) mice than in wild types, whereas no differences were observed throughout the [K(+)]o recovery phase. In stratum pyramidale and corpus callosum, neither peak [K(+)]o nor post-stimulus [K(+)]o recovery was affected by Aqp4 deletion. Our data suggest that AQP4 modulates [K(+)]o during synaptic stimulation through its effect on extracellular space volume.
    Brain Structure and Function 04/2014; 220(4). DOI:10.1007/s00429-014-0767-z · 4.57 Impact Factor
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    ABSTRACT: Despite large gains in health over the past few decades, the distribution of health risks worldwide remains extremely and unacceptably uneven. Although the health sector has a crucial role in addressing health inequalities, its efforts often come into conflict with powerful global actors in pursuit of other interests such as protection of national security, safeguarding of sovereignty, or economic goals. This is the starting point of The Lancet-University of Oslo Commission on Global Governance for Health. With globalisation, health inequity increasingly results from transnational activities that involve actors with different interests and degrees of power: states, transnational corporations, civil society, and others. The decisions, policies, and actions of such actors are, in turn, founded on global social norms. Their actions are not designed to harm health, but can have negative side-effects that create health inequities. The norms, policies, and practices that arise from global political interaction across all sectors that affect health are what we call global political determinants of health. The Commission argues that global political determinants that unfavourably affect the health of some groups of people relative to others are unfair, and that at least some harms could be avoided by improving how global governance works. There is an urgent need to understand how public health can be better protected and promoted in the realm of global governance, but this issue is a complex and politically sensitive one. Global governance processes involve the distribution of economic, intellectual, normative, and political resources, and to assess their effect on health requires an analysis of power. This report examines power disparities and dynamics across a range of policy areas that aff ect health and that require improved global governance: economic crises and austerity measures, knowledge and intellectual property, foreign investment treaties, food security, transnational corporate activity, irregular migration, and violent conflict. The case analyses show that in the contemporary global governance landscape, power asymmetries between actors with conflicting interests shape political determinants of health. We identified five dysfunctions of the global governance system that allow adverse eff ects of global political determinants of health to persist. First, participation and representation of some actors, such as civil society, health experts, and marginalised groups, are insufficient in decision-making processes (democratic deficit). Second, inadequate means to constrain power and poor transparency make it difficult to hold actors to account for their actions (weak accountability mechanisms). Third, norms, rules, and decision-making procedures are often impervious to changing needs and can sustain entrenched power disparities, with adverse eff ects on the distribution of health (institutional stickiness). Fourth, inadequate means exist at both national and global levels to protect health in global policy-making arenas outside of the health sector, such that health can be subordinated under other objectives (inadequate policy space for health). Lastly, in a range of policy-making areas, there is a total or near absence of international institutions (eg, treaties, funds, courts, and softer forms of regulation such as norms and guidelines) to protect and promote health (missing or nascent institutions). Recognising that major drivers of ill health lie beyond the control of national governments and, in many instances, also outside of the health sector, we assert that some of the root causes of health inequity must be addressed within global governance processes. For the continued success of the global health system, its initiatives must not be thwarted by political decisions in other arenas. Rather, global governance processes outside the health arena must be made to work better for health. The Commission calls for stronger cross-sectoral global action for health. We propose for consideration a Multistakeholder Platform on Governance for Health, which would serve as a policy forum to provide space for diverse stakeholders to frame issues, set agendas, examine and debate policies in the making that would have an eff ect on health and health equity, and identify barriers and propose solutions for concrete policy processes. Additionally, we call for the independent monitoring of how global governance processes aff ect health equity to be institutionalised through an Independent Scientific Monitoring Panel and mandated health equity impact assessments within international organisations. The Commission also calls for measures to better harness the global political determinants of health. We call for strengthened use of human rights instruments for health, such as the Special Rapporteurs, and stronger sanctions against a broader range of violations by nonstate actors through the international judicial system. We recognise that global governance for health must be rooted in commitments to global solidarity and shared responsibility through rights-based approaches and new frameworks for international financing that go beyond traditional development assistance, such as for research and social protection. We want to send a strong message to the international community and to all actors that exert influence in processes of global governance: we must no longer regard health only as a technical biomedical issue, but acknowledge the need for global cross-sectoral action and justice in our eff orts to address health inequity.
    The Lancet 02/2014; 383(9917). DOI:10.1016/S0140-6736(13)62407-1 · 45.22 Impact Factor
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    ABSTRACT: The focal swellings of dendrites (dendritic beading) are an early morphological hallmark of neuronal injury and dendrotoxicity. They are associated with a variety of pathological conditions including brain ischemia and cause an acute disruption of synaptic transmission and neuronal network function, which contributes to subsequent neuronal death. Here we show that increased synaptic activity prior to excitotoxic injury protects, in a transcription-dependent manner, against dendritic beading. Expression of Activating transcription factor 3 (ATF3), a nuclear calcium-regulated gene and member of the core gene program for acquired neuroprotection, can protect against dendritic beading. Conversely, knock-down of ATF3 exacerbates dendritic beading. Assessment of neuronal network functions using multi-electrode array recordings revealed that hippocampal neurons expressing ATF3 were able to regain their ability of functional synaptic transmission and to participate in coherent neuronal network activity within 48 h after exposure to toxic concentrations of NMDA. Thus, in addition to attenuating cell death, synaptic activity and expression of ATF3 render hippocampal neurons more resistant to acute dendrotoxicity and loss of synapses. Dendroprotection can enhance recovery of neuronal network functions after excitotoxic insults.
    Journal of Biological Chemistry 02/2014; 289(14). DOI:10.1074/jbc.M113.502914 · 4.57 Impact Factor
  • Erlend A Nagelhus · Ole P Ottersen
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    ABSTRACT: Aquaporin-4 (AQP4) is one of the most abundant molecules in the brain and is particularly prevalent in astrocytic membranes at the blood-brain and brain-liquor interfaces. While AQP4 has been implicated in a number of pathophysiological processes, its role in brain physiology has remained elusive. Only recently has evidence accumulated to suggest that AQP4 is involved in such diverse functions as regulation of extracellular space volume, potassium buffering, cerebrospinal fluid circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, and Ca(2+) signaling. AQP4 is also required for normal function of the retina, inner ear, and olfactory system. A review will be provided of the physiological roles of AQP4 in brain and of the growing list of data that emphasize the polarized nature of astrocytes.
    Physiological Reviews 10/2013; 93(4):1543-62. DOI:10.1152/physrev.00011.2013 · 29.04 Impact Factor
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    ABSTRACT: Aquaporin-4 (AQP4) is the primary cellular water channel in the brain and is abundantly expressed by astrocytes along the blood-brain barrier and brain-cerebrospinal fluid interfaces. Water transport via AQP4 contributes to the activity-dependent volume changes of the extracellular space (ECS), which affect extracellular solute concentrations and neuronal excitability. AQP4 is anchored by α-syntrophin (α-syn), the deletion of which leads to reduced AQP4 levels in perivascular and subpial membranes. We used the real-time iontophoretic method and/or diffusion-weighted magnetic resonance imaging to clarify the impact of α-syn deletion on astrocyte morphology and changes in extracellular diffusion associated with cell swelling in vitro and in vivo. In mice lacking α-syn, we found higher resting values of the apparent diffusion coefficient of water (ADCW) and the extracellular volume fraction (α). No significant differences in tortuosity (λ) or non-specific uptake (k'), were found between α-syn-negative (α-syn -/-) and α-syn-positive (α-syn +/+) mice. The deletion of α-syn resulted in a significantly smaller relative decrease in α observed during elevated K(+) (10 mM) and severe hypotonic stress (-100 mOsmol/l), but not during mild hypotonic stress (-50 mOsmol/l). After the induction of terminal ischemia/anoxia, the final values of ADCW as well as of the ECS volume fraction α indicate milder cell swelling in α-syn -/- in comparison with α-syn +/+ mice. Shortly after terminal ischemia/anoxia induction, the onset of a steep rise in the extracellular potassium concentration and an increase in λ was faster in α-syn -/- mice, but the final values did not differ between α-syn -/- and α-syn +/+ mice. This study reveals that water transport through AQP4 channels enhances and accelerates astrocyte swelling. The substantially altered ECS diffusion parameters will likely affect the movement of neuroactive substances and/or trophic factors, which in turn may modulate the extent of tissue damage and/or drug distribution.
    PLoS ONE 07/2013; 8(7):e68044. DOI:10.1371/journal.pone.0068044 · 3.23 Impact Factor
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    ABSTRACT: It has been suggested that loss of the astrocytic water channel aquaporin-4 (AQP4) from perivascular endfeet in sclerotic hippocampi contributes to increased seizure propensity in human mesial temporal lobe epilepsy (MTLE). Whether this loss occurs prior to or as a consequence of epilepsy development remains to be resolved. In the present study, we investigated whether the expression and distribution of AQP4 was altered prior to (i.e., in the latent phase) or after the onset of chronic epileptic seizures (i.e., in the chronic phase) in the kainate (KA) model of MTLE. Immunogold electron microscopic analysis revealed that AQP4 density in adluminal endfoot membranes was reduced in KA treated rats already in the latent phase, while the AQP4 density in the abluminal endfoot membrane was stable or slightly increased. The decrease in adluminal AQP4 immunogold labeling was accompanied by a reduction in the density of AQP4's anchoring protein alpha-syntrophin. The latent and chronic phases were associated with an upregulation of the M1 isoform of AQP4, as judged by semi-quantitative Western blot analysis. Taken together, the findings in this model suggest that a mislocalization of AQP4 - reflecting a loss of astrocyte polarization - is an integral part of the epileptogenic process.
    Epilepsy research 07/2013; 105(1-2). DOI:10.1016/j.eplepsyres.2013.01.006 · 2.19 Impact Factor
  • Mahmood Amiry-Moghaddam · Ole Petter Ottersen
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    ABSTRACT: The complexity of the central nervous system calls for immunocytochemical procedures that allow target proteins to be localized with high precision and with opportunities for quantitation. Immunogold procedures stand out as particularly powerful in this regard. Although these procedures have found wide application in the neuroscience community, they present limitations and pitfalls that must be taken into account. At the same time, these procedures offer potentials that remain to be fully realized.
    Nature Neuroscience 06/2013; 16(7):798-804. DOI:10.1038/nn.3418 · 14.98 Impact Factor
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    ABSTRACT: Aquaporin 4 (AQP4) is the predominant water channel in the brain, expressed mainly in astrocytes and involved in water transport in physiologic and pathologic conditions. Besides the classical isoforms M1 (a) and M23 (c), additional ones may be present at the plasma membrane, such as the recently described AQP4b, d, e, and f. Water permeability regulation by AQP4 isoforms may involve several processes, such as channel conformational changes, the extent and arrangement of channels at the plasma membrane, and the dynamics of channel trafficking to/from the plasma membrane. To test whether vesicular trafficking affects the abundance of AQP4 channel at the plasma membrane, we studied the subcellular localization of AQP4 in correlation with vesicle mobility of AQP4e, one of the newly discovered AQP4 isoforms. In cultured rat astrocytes, recombinant AQP4e acquired plasma membrane localization, which resembled that of the antibody labeled endogenous AQP4 localization. Under conditions mimicking reactivation of astrocytes (increase in cytosolic cAMP) and brain edema, an increase in the AQP4 plasma membrane localization was observed. The cytoskeleton remained unaffected with the exception of rearranged actin filaments in the model of reactive astrocytes and vimentin meshwork depolymerization in hypoosmotic conditions. AQP4e vesicle mobility correlated with changes in the plasma membrane localization of AQP4 in all stimulated conditions. Hypoosmotic stimulation triggered a transient reduction in AQP4e vesicle mobility mirrored by the transient changes in AQP4 plasma membrane localization. We suggest that regulation of AQP4 surface expression in pathologic conditions is associated with the mobility of AQP4-carrying vesicles.
    Glia 06/2013; 61(6). DOI:10.1002/glia.22485 · 6.03 Impact Factor
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    ABSTRACT: Using in vivo two-photon imaging, we show that mice deficient in aquaporin-4 (AQP4) display increased fluorescence of nicotinamide adenine dinucleotide (NADH) when subjected to cortical spreading depression. The increased NADH signal, a proxy of tissue hypoxia, was restricted to microwatershed areas remote from the vasculature. Aqp4 deletion had no effects on the hyperemia response, but slowed [K(+)]o recovery. These observations suggest that K(+) uptake is suppressed in Aqp4(-/-) mice as a consequence of decreased oxygen delivery to tissue located furthest away from the vascular source of oxygen, although increased oxygen consumption may also contribute to our observations.Journal of Cerebral Blood Flow & Metabolism advance online publication, 24 April 2013; doi:10.1038/jcbfm.2013.63.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2013; 33. DOI:10.1038/jcbfm.2013.63 · 5.34 Impact Factor
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    ABSTRACT: It has been suggested that loss of the astrocytic water channel aquaporin-4 (AQP4) from perivascular endfeet in sclerotic hippocampi contributes to increased seizure propensity in human mesial temporal lobe epilepsy (MTLE). Whether this loss occurs prior to or as a consequence of epilepsy development remains to be resolved. In the present study, we investigated whether the expression and distribution of AQP4 was altered prior to (i.e., in the latent phase) or after the onset of chronic epileptic seizures (i.e., in the chronic phase) in the kainate (KA) model of MTLE. Immunogold electron microscopic analysis revealed that AQP4 density in adluminal endfoot membranes was reduced in KA treated rats already in the latent phase, while the AQP4 density in the abluminal endfoot membrane was stable or slightly increased. The decrease in adluminal AQP4 immunogold labeling was accompanied by a reduction in the density of AQP4's anchoring protein alpha-syntrophin. The latent and chronic phases were associated with an upregulation of the M1 isoform of AQP4, as judged by semi-quantitative Western blot analysis. Taken together, the findings in this model suggest that a mislocalization of AQP4 - reflecting a loss of astrocyte polarization - is an integral part of the epileptogenic process.
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    ABSTRACT: Key roles of macroglia are inextricably coupled to specialized membrane domains. The perivascular endfoot membrane has drawn particular attention, as this domain contains a unique complement of aquaporin-4 (AQP4) and other channel proteins that distinguishes it from perisynaptic membranes. Recent studies indicate that the polarization of macroglia is lost in a number of diseases, including temporal lobe epilepsy and Alzheimer's disease. A better understanding is required of the molecular underpinning of astroglial polarization, particularly when it comes to the significance of the dystrophin associated protein complex (DAPC). Here, we employ immunofluorescence and immunogold cytochemistry to analyze the molecular scaffolding in perivascular endfeet in macroglia of retina and three regions of brain (cortex, dentate gyrus, and cerebellum), using AQP4 as a marker. Compared with brain astrocytes, Müller cells (a class of retinal macroglia) exhibit lower densities of the scaffold proteins dystrophin and α-syntrophin (a DAPC protein), but higher levels of AQP4. In agreement, depletion of dystrophin or α-syntrophin-while causing a dramatic loss of AQP4 from endfoot membranes of brain astrocytes-had only modest or insignificant effect, respectively, on the AQP4 pool in endfoot membranes of Müller cells. In addition, while polarization of brain macroglia was less affected by dystrophin depletion than by targeted deletion of α-syntrophin, the reverse was true for retinal macroglia. These data indicate that the molecular scaffolding in perivascular endfeet is more complex than previously assumed and that macroglia are heterogeneous with respect to the mechanisms that dictate their polarization. © 2012 Wiley Periodicals, Inc.
    Glia 12/2012; 60(12):2018-26. DOI:10.1002/glia.22416 · 6.03 Impact Factor
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    ABSTRACT: Aquaporins (AQPs) are channel-forming membrane proteins highly permeable to water. AQP4 is found in mammalian hearts; however, its expression sites, regulation and function are largely unknown. The aim was to investigate cardiac AQP4 expression in humans and mice, its regulation by ischemia and hypoxia, and in particular its role in cardiac ischemic injury using AQP4 knockout (KO) mice. Comparable levels of AQP4 were detected by Western blot and qPCR in biopsies from human donor hearts and wild type C57Bl6 mouse hearts. In mice, AQP4 was expressed on cardiomyocyte plasmalemma (qPCR, Western blot, immunogold), and its mRNA decreased following ischemia/reperfusion (isolated hearts, p = 0.02) and after normobaric hypoxia in vivo (oxygen fraction 10 % for 1 week, p < 0.001). Isolated hearts from AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size (p = 0.05) and attenuated left ventricular end-diastolic pressure during reperfusion (p = 0.04). Infarct size was also reduced in AQP4 KO mice 24 h after left coronary artery ligation in vivo (p = 0.036). AQP4 KO hearts had no compensatory change in AQP1 protein expression. AQP4 KO cardiomyocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture. AQP4 is expressed in human and mouse hearts, in the latter confined to the cardiomyocyte plasmalemma. AQP4 mRNA expression is downregulated by hypoxia and ischemia. Deletion of AQP4 is protective in acute myocardial ischemia-reperfusion, and this molecule might be a future target in the treatment of acute myocardial infarction.
    Archiv für Kreislaufforschung 09/2012; 107(5):280. DOI:10.1007/s00395-012-0280-6 · 5.96 Impact Factor
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    ABSTRACT: Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of β-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.
    Journal of Neuropathology and Experimental Neurology 08/2012; 71(9):814-25. DOI:10.1097/NEN.0b013e318267b5af · 4.37 Impact Factor

Publication Stats

25k Citations
1,851.31 Total Impact Points

Institutions

  • 1970–2015
    • University of Oslo
      • • Department of Anatomy
      • • Centre for Molecular Biology and Neuroscience
      • • Institute of Basic Medical Sciences
      Kristiania (historical), Oslo, Norway
  • 2005
    • Center for Autism and Related Disorders
      Burbank, California, United States
  • 2004
    • Yale University
      • Department of Neurosurgery
      New Haven, CT, United States
  • 2003
    • Humboldt-Universität zu Berlin
      • Institute of Finance
      Berlín, Berlin, Germany
  • 2002
    • Shinshu University
      • Department of Otorhinolaryngology
      Shonai, Nagano, Japan
  • 1995
    • Karolinska Institutet
      • Institutionen för neurovetenskap
      Solna, Stockholm, Sweden
  • 1990
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1988
    • Freie Universität Berlin
      Berlín, Berlin, Germany
    • Harvard University
      • Department of Developmental Biology
      Cambridge, Massachusetts, United States
    • University of Bristol
      Bristol, England, United Kingdom