Tumor Necrosis Factor-α Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure
Identifieur interne : 001B59 ( Ncbi/Merge ); précédent : 001B58; suivant : 001B60Tumor Necrosis Factor-α Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure
Auteurs : Anja Meissner ; Naomi P. Visanji ; M Abdul Momen ; Rui Feng ; Beverly M. Francis ; Steffen-Sebastian Bolz ; Lili-Naz HazratiSource :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease [ 2047-9980 ] ; 2015.
Abstract
Heart failure (HF) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor-α (TNF-α)–dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early HF in which blood pressure remains minimally affected. HF is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of cognitive impairments in HF is unknown, and appropriate treatment strategies are lacking.
We used a well-established mouse model in which HF was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size ≈25% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8 weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine TNF-α during HF-mediated neuroinflammation and associated impaired hippocampus-independent nonspatial episodic memory function. Augmented cerebral TNF-α expression and microglial activation in HF mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39±8.61% for basal and 61.04±9.18% for apical spines [
Our findings demonstrate that TNF-α plays a pivotal role in HF-mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for HF-associated memory deficits.
Url:
DOI: 10.1161/JAHA.115.001920
PubMed: 25948533
PubMed Central: 4599420
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Tumor Necrosis Factor-α Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure</title>
<author><name sortKey="Meissner, Anja" sort="Meissner, Anja" uniqKey="Meissner A" first="Anja" last="Meissner">Anja Meissner</name>
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<author><name sortKey="Momen, M Abdul" sort="Momen, M Abdul" uniqKey="Momen M" first="M Abdul" last="Momen">M Abdul Momen</name>
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<author><name sortKey="Francis, Beverly M" sort="Francis, Beverly M" uniqKey="Francis B" first="Beverly M" last="Francis">Beverly M. Francis</name>
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<author><name sortKey="Bolz, Steffen Sebastian" sort="Bolz, Steffen Sebastian" uniqKey="Bolz S" first="Steffen-Sebastian" last="Bolz">Steffen-Sebastian Bolz</name>
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<author><name sortKey="Hazrati, Lili Naz" sort="Hazrati, Lili Naz" uniqKey="Hazrati L" first="Lili-Naz" last="Hazrati">Lili-Naz Hazrati</name>
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<series><title level="j">Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</title>
<idno type="ISSN">2047-9980</idno>
<idno type="eISSN">2047-9980</idno>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Heart failure (HF) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor-α (TNF-α)–dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early HF in which blood pressure remains minimally affected. HF is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of cognitive impairments in HF is unknown, and appropriate treatment strategies are lacking.</p>
</sec>
<sec><title>Methods and Results</title>
<p>We used a well-established mouse model in which HF was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size ≈25% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8 weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine TNF-α during HF-mediated neuroinflammation and associated impaired hippocampus-independent nonspatial episodic memory function. Augmented cerebral TNF-α expression and microglial activation in HF mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39±8.61% for basal and 61.04±9.18% for apical spines [<italic>P</italic>
<0.001]). The significance of TNF-α signaling during the observed HF-mediated neurodegenerative processes is supported by evidence showing that sequestration or genetic deletion of TNF-α ameliorates the observed reduction of cortical dendritic spines (33.51±7.63% for basal and 30.13±6.98% for apical spines in wild-type mice treated with etanercept; 17.09±6.81% for basal and 17.21±7.29% for apical spines in TNF-α<sup>−/−</sup>
). Moreover, our data suggest that alterations in cerebral serum and glucocorticoid-inducible kinase 1 (SgK1) expression and phosphorylation during HF may be TNF-α dependent and that an increase of SgK1 phosphorylation potentially plays a role in the HF-associated reduction of dendritic spine density.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our findings demonstrate that TNF-α plays a pivotal role in HF-mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for HF-associated memory deficits.</p>
</sec>
</div>
</front>
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</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Am Heart Assoc</journal-id>
<journal-id journal-id-type="iso-abbrev">J Am Heart Assoc</journal-id>
<journal-id journal-id-type="publisher-id">jah3</journal-id>
<journal-title-group><journal-title>Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</journal-title>
</journal-title-group>
<issn pub-type="ppub">2047-9980</issn>
<issn pub-type="epub">2047-9980</issn>
<publisher><publisher-name>John Wiley & Sons, Ltd</publisher-name>
<publisher-loc>Chichester, UK</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25948533</article-id>
<article-id pub-id-type="pmc">4599420</article-id>
<article-id pub-id-type="doi">10.1161/JAHA.115.001920</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Tumor Necrosis Factor-α Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Meissner</surname>
<given-names>Anja</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="corresp" rid="cor1"></xref>
<xref ref-type="aff" rid="au1"></xref>
<xref ref-type="aff" rid="au7"></xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Visanji</surname>
<given-names>Naomi P</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au2"></xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Momen</surname>
<given-names>M Abdul</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feng</surname>
<given-names>Rui</given-names>
</name>
<degrees>BSc</degrees>
<xref ref-type="aff" rid="au4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Francis</surname>
<given-names>Beverly M</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bolz</surname>
<given-names>Steffen-Sebastian</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au1"></xref>
<xref ref-type="aff" rid="au5"></xref>
<xref ref-type="aff" rid="au6"></xref>
<xref ref-type="author-notes" rid="fn2">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hazrati</surname>
<given-names>Lili-Naz</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au4"></xref>
<xref ref-type="author-notes" rid="fn2">†</xref>
</contrib>
<aff id="au1"><institution>Department of Physiology, University of Toronto</institution>
<addr-line>Ontario, Canada (A.M., S.-S.B.)</addr-line>
</aff>
<aff id="au2"><institution>Morten and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital</institution>
<addr-line>Toronto, Ontario, Canada (N.P.V.)</addr-line>
</aff>
<aff id="au3"><institution>Division of Cell and Molecular Biology, Toronto General Hospital Research Institute</institution>
<addr-line>Toronto, Ontario, Canada (M.A.M.)</addr-line>
</aff>
<aff id="au4"><institution>Tanz Center for Research in Neurodegenerative Diseases</institution>
<addr-line>Toronto, Ontario, Canada (R.F., B.M.F., L.-N.H.)</addr-line>
</aff>
<aff id="au5"><institution>Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research</institution>
<addr-line>Toronto, Ontario, Canada (S.-S.B.)</addr-line>
</aff>
<aff id="au6"><institution>Toronto Centre for Microvascular Medicine, University of Toronto, and Li Ka Shing Knowledge Institute at St Michael’s Hospital</institution>
<addr-line>Toronto, Ontario, Canada (S.-S.B.)</addr-line>
</aff>
<aff id="au7"><institution>Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)</institution>
<addr-line>Barcelona, Spain (A.M.)</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><bold>Correspondence to:</bold>
Anja Meissner, PhD, Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosello 161 (6th floor), 08036 Barcelona, Spain. E-mail: <email>anja.meissner@gmail.com</email>
</corresp>
<fn id="fn1"><label>*</label>
<p>Dr Meissner and Dr Visanji contributed equally to the work as first authors.</p>
</fn>
<fn id="fn2"><label>†</label>
<p>Dr Bolz and Dr Hazrati contributed equally to the work as senior authors.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>5</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>06</day>
<month>5</month>
<year>2015</year>
</pub-date>
<volume>4</volume>
<issue>5</issue>
<elocation-id>e001920</elocation-id>
<history><date date-type="received"><day>10</day>
<month>2</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>11</day>
<month>4</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</license-p>
</license>
</permissions>
<abstract><sec><title>Background</title>
<p>Heart failure (HF) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor-α (TNF-α)–dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early HF in which blood pressure remains minimally affected. HF is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of cognitive impairments in HF is unknown, and appropriate treatment strategies are lacking.</p>
</sec>
<sec><title>Methods and Results</title>
<p>We used a well-established mouse model in which HF was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size ≈25% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8 weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine TNF-α during HF-mediated neuroinflammation and associated impaired hippocampus-independent nonspatial episodic memory function. Augmented cerebral TNF-α expression and microglial activation in HF mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39±8.61% for basal and 61.04±9.18% for apical spines [<italic>P</italic>
<0.001]). The significance of TNF-α signaling during the observed HF-mediated neurodegenerative processes is supported by evidence showing that sequestration or genetic deletion of TNF-α ameliorates the observed reduction of cortical dendritic spines (33.51±7.63% for basal and 30.13±6.98% for apical spines in wild-type mice treated with etanercept; 17.09±6.81% for basal and 17.21±7.29% for apical spines in TNF-α<sup>−/−</sup>
). Moreover, our data suggest that alterations in cerebral serum and glucocorticoid-inducible kinase 1 (SgK1) expression and phosphorylation during HF may be TNF-α dependent and that an increase of SgK1 phosphorylation potentially plays a role in the HF-associated reduction of dendritic spine density.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our findings demonstrate that TNF-α plays a pivotal role in HF-mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for HF-associated memory deficits.</p>
</sec>
</abstract>
<kwd-group><kwd>heart failure</kwd>
<kwd>inflammation</kwd>
<kwd>nervous system</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Bolz, Steffen Sebastian" sort="Bolz, Steffen Sebastian" uniqKey="Bolz S" first="Steffen-Sebastian" last="Bolz">Steffen-Sebastian Bolz</name>
<name sortKey="Feng, Rui" sort="Feng, Rui" uniqKey="Feng R" first="Rui" last="Feng">Rui Feng</name>
<name sortKey="Francis, Beverly M" sort="Francis, Beverly M" uniqKey="Francis B" first="Beverly M" last="Francis">Beverly M. Francis</name>
<name sortKey="Hazrati, Lili Naz" sort="Hazrati, Lili Naz" uniqKey="Hazrati L" first="Lili-Naz" last="Hazrati">Lili-Naz Hazrati</name>
<name sortKey="Meissner, Anja" sort="Meissner, Anja" uniqKey="Meissner A" first="Anja" last="Meissner">Anja Meissner</name>
<name sortKey="Momen, M Abdul" sort="Momen, M Abdul" uniqKey="Momen M" first="M Abdul" last="Momen">M Abdul Momen</name>
<name sortKey="Visanji, Naomi P" sort="Visanji, Naomi P" uniqKey="Visanji N" first="Naomi P" last="Visanji">Naomi P. Visanji</name>
</noCountry>
</tree>
</affiliations>
</record>
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