Connexin40 regulates platelet function
Identifieur interne : 000097 ( Pmc/Curation ); précédent : 000096; suivant : 000098Connexin40 regulates platelet function
Auteurs : Sakthivel Vaiyapuri [Royaume-Uni] ; Leonardo A. Moraes [Royaume-Uni] ; Tanya Sage [Royaume-Uni] ; Marfoua S. Ali [Royaume-Uni] ; Kirsty R. Lewis [Royaume-Uni] ; Martyn P. Mahaut-Smith [Royaume-Uni] ; Ernesto Oviedo-Orta [Royaume-Uni] ; Alexander M. Simon [États-Unis] ; Jonathan M. Gibbins [Royaume-Uni]Source :
- Nature Communications [ 2041-1723 ] ; 2013.
Abstract
The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor 37,43Gap27 on
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DOI: 10.1038/ncomms3564
PubMed: 24096827
PubMed Central: 3806366
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Gibbins</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24096827</idno><idno type="pmc">3806366</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806366</idno><idno type="RBID">PMC:3806366</idno><idno type="doi">10.1038/ncomms3564</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000097</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000097</idno><idno type="wicri:Area/Pmc/Curation">000097</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000097</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Connexin40 regulates platelet function</title><author><name sortKey="Vaiyapuri, Sakthivel" sort="Vaiyapuri, Sakthivel" uniqKey="Vaiyapuri S" first="Sakthivel" last="Vaiyapuri">Sakthivel Vaiyapuri</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Moraes, Leonardo A" sort="Moraes, Leonardo A" uniqKey="Moraes L" first="Leonardo A." last="Moraes">Leonardo A. Moraes</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sage, Tanya" sort="Sage, Tanya" uniqKey="Sage T" first="Tanya" last="Sage">Tanya Sage</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ali, Marfoua S" sort="Ali, Marfoua S" uniqKey="Ali M" first="Marfoua S." last="Ali">Marfoua S. Ali</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lewis, Kirsty R" sort="Lewis, Kirsty R" uniqKey="Lewis K" first="Kirsty R." last="Lewis">Kirsty R. Lewis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mahaut Smith, Martyn P" sort="Mahaut Smith, Martyn P" uniqKey="Mahaut Smith M" first="Martyn P." last="Mahaut-Smith">Martyn P. Mahaut-Smith</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Cell Physiology and Pharmacology, University of Leicester</institution>, Leicester, LE1 9HN,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Oviedo Orta, Ernesto" sort="Oviedo Orta, Ernesto" uniqKey="Oviedo Orta E" first="Ernesto" last="Oviedo-Orta">Ernesto Oviedo-Orta</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Faculty of Health and Medical Sciences, Cardiovascular Biology Research, University of Surrey</institution>, Guildford GU2 7XH,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Simon, Alexander M" sort="Simon, Alexander M" uniqKey="Simon A" first="Alexander M." last="Simon">Alexander M. Simon</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Physiology, University of Arizona</institution>, Tucson, Arizona 85724-5051,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gibbins, Jonathan M" sort="Gibbins, Jonathan M" uniqKey="Gibbins J" first="Jonathan M." last="Gibbins">Jonathan M. Gibbins</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor <sup>37,43</sup>Gap27 on <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets and of the Cx40 inhibitor <sup>40</sup>Gap27 on <italic>Cx37</italic><sup><italic>−/−</italic></sup> mouse platelets revealed that each connexin is able to function independently. Inhibition or deletion of Cx40 reduces haemostatic responses in mice, indicating the physiological importance of this protein in platelets. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Pub. Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24096827</article-id><article-id pub-id-type="pmc">3806366</article-id><article-id pub-id-type="pii">ncomms3564</article-id><article-id pub-id-type="doi">10.1038/ncomms3564</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Connexin40 regulates platelet function</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Vaiyapuri</surname><given-names>Sakthivel</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Moraes</surname><given-names>Leonardo A.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sage</surname><given-names>Tanya</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ali</surname><given-names>Marfoua S.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lewis</surname><given-names>Kirsty R.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mahaut-Smith</surname><given-names>Martyn P.</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Oviedo-Orta</surname><given-names>Ernesto</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Simon</surname><given-names>Alexander M.</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gibbins</surname><given-names>Jonathan M.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><aff id="a1"><label>1</label><institution>Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading</institution>, Harborne Building, Whiteknights, RG6 6AS Reading,<country>UK</country></aff><aff id="a2"><label>2</label><institution>Department of Cell Physiology and Pharmacology, University of Leicester</institution>, Leicester, LE1 9HN,<country>UK</country></aff><aff id="a3"><label>3</label><institution>Faculty of Health and Medical Sciences, Cardiovascular Biology Research, University of Surrey</institution>, Guildford GU2 7XH,<country>UK</country></aff><aff id="a4"><label>4</label><institution>Department of Physiology, University of Arizona</institution>, Tucson, Arizona 85724-5051,<country>USA</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>j.m.gibbins@reading.ac.uk</email></corresp></author-notes><pub-date pub-type="epub"><day>07</day><month>10</month><year>2013</year></pub-date><volume>4</volume><elocation-id>2564</elocation-id><history><date date-type="received"><day>17</day><month>07</month><year>2013</year></date><date date-type="accepted"><day>06</day><month>09</month><year>2013</year></date></history><permissions><copyright-statement>Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/</license-p></license></permissions><abstract><p>The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor <sup>37,43</sup>Gap27 on <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets and of the Cx40 inhibitor <sup>40</sup>Gap27 on <italic>Cx37</italic><sup><italic>−/−</italic></sup> mouse platelets revealed that each connexin is able to function independently. Inhibition or deletion of Cx40 reduces haemostatic responses in mice, indicating the physiological importance of this protein in platelets. We conclude that multiple connexins are involved in regulating platelet function, thereby contributing to haemostasis and thrombosis.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms3564-i1.jpg"></inline-graphic>Hemichannels and gap junctions containing the connexin Cx37 are required for platelet functions such as aggregation and granule secretion through poorly defined mechanisms. Vaiyapuri <italic>et al</italic>. show that Cx40 is also required and can act independently of Cx37 in mouse platelets.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Presence of Cx40 and effects of its inhibition on platelet function.</title><p>(<bold>a</bold>) Presence of Cx40 in human platelets was confirmed by immunoblot analysis (human umbilical vascular endothelial cells (<bold>a</bold>), and resting (<bold>b</bold>) or CRP-XL- (1 μg ml<sup>−1</sup>) stimulated human platelets (<bold>c</bold>)). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was detected as a loading control. Human platelet aggregation performed in the presence or absence of <sup>40</sup>Gap27 was recorded for 90 s following stimulation with 0.5 (<bold>b</bold>,<bold>c</bold>) or 1 μg ml<sup>−1</sup> (<bold>d</bold>,<bold>e</bold>) CRP-XL (a scrambled peptide control showed no effect on aggregation compared with the vehicle (<bold>f</bold>,<bold>g</bold>)), 0.1 U ml<sup>−1</sup> thrombin (<bold>h</bold>,<bold>i</bold>) and 10 μM ADP (<bold>j</bold>,<bold>k</bold>). Cumulative data represent mean±s.d. (<italic>n</italic>=4). The level of aggregation obtained with vehicle was taken as 100% (Student’s <italic>t</italic>-test, *<italic>P</italic><0.05 and **<italic>P</italic><0.01).</p></caption><graphic xlink:href="ncomms3564-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Deletion of <italic>Cx40</italic> affects platelet activation.</title><p>Deletion of <italic>Cx40</italic> was confirmed in <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets by immunoblotting (<bold>a</bold>). The expression of <italic>Cx32</italic> (<bold>b</bold>), <italic>Cx37</italic> (<bold>c</bold>) and <italic>Cx43</italic> (<bold>d</bold>) were analysed by immunoblot analysis using <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets. 14-3-3ζ was detected as a loading control. Blots are representative of four separate experiments. The expression levels of αIIbβ3 (<bold>e</bold>), α<sub>2</sub>β<sub>1</sub> (<bold>f</bold>), GPVI (<bold>g</bold>) and GPIbα (<bold>h</bold>) were analysed on <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets by flow cytometry. Platelet aggregation performed in the presence or absence of <sup>40</sup>Gap27 using washed platelets obtained from <italic>Cx40</italic><sup><italic>+/+</italic></sup> (<bold>i</bold>) and <italic>Cx40</italic><sup><italic>−/−</italic></sup> (<bold>j</bold>) mice was recorded for 180 s following stimulation with CRP-XL (0.5 μg ml<sup>−1</sup>). The level of aggregation obtained in the absence of <sup>40</sup>Gap27 was taken as 100%. Similar aggregations were performed using washed platelets obtained from <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> mice following stimulation with 0.5 (<bold>k</bold>,<bold>l</bold>) or 1 μg ml<sup>−1</sup> CRP-XL (<bold>m</bold>,<bold>n</bold>). Data represent mean±s.d. (<italic>n</italic>=4). The level of aggregation obtained with <italic>Cx40</italic><sup><italic>+/+</italic></sup> was taken as 100% (Student’s <italic>t</italic>-test, *<italic>P</italic><0.05 and **<italic>P</italic><0.01).</p></caption><graphic xlink:href="ncomms3564-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Inhibition or deletion of Cx40 reduces platelet inside-out signalling and granule secretion.</title><p>The effect of <sup>40</sup>Gap27 on 1 μg ml<sup>−1</sup> CRP-XL- (<bold>a</bold>), 10 μM ADP- (<bold>b</bold>) and 0.1 U ml<sup>−1</sup> thrombin- (<bold>c</bold>) induced fibrinogen binding was measured by flow cytometry using human PRP. Similarly, fibrinogen binding to <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets was measured using whole blood following stimulation with 1 μg ml<sup>−1</sup> CRP-XL (<bold>d</bold>). Fibrinogen binding obtained with vehicle or <italic>Cx40</italic><sup><italic>+/+</italic></sup> was taken as 100%. Human PRP was stimulated with 1 μg ml<sup>−1</sup> CRP-XL (<bold>e</bold>), 10 μM ADP (<bold>f</bold>) and 0.1 U ml<sup>−1</sup> thrombin (<bold>g</bold>) in the presence and absence of <sup>40</sup>Gap27 (100 μg ml<sup>−1</sup>) and the level of P-selectin exposed on surface measured by flow cytometry. Similarly, P-Selectin exposure upon stimulation with 1 μg ml<sup>−1</sup> CRP-XL using whole blood obtained from <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> was measured (<bold>h</bold>). P-selectin exposure with vehicle or <italic>Cx40</italic><sup><italic>+/+</italic></sup> was taken as 100%. Human washed platelets were stimulated with 0.5 μg ml<sup>−1</sup> CRP-XL in the presence and absence of <sup>40</sup>Gap27 (100 μg ml<sup>−1</sup>), and the level of ATP secretion was measured using lumino-aggregometry (<bold>i</bold>,<bold>j</bold>). Data represent mean±s.d. (<italic>n</italic>=4; Student’s <italic>t</italic>-test, *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001).</p></caption><graphic xlink:href="ncomms3564-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Inhibitory effects of <sup>40</sup>Gap27 on platelet function are not solely due to defects in granule secretion or TXA<sub>2</sub> synthesis.</title><p>The level of fibrinogen binding was measured in the presence and absence of apyrase (4 U ml<sup>−1</sup>) or indomethacin (20 μM), or both (at the same concentration) on 0.5 (<bold>a</bold>) and 1 μg ml<sup>−1</sup> (<bold>b</bold>) CRP-XL activation in human PRP. The level of fibrinogen binding obtained in the absence of apyrase or indomethacin was taken as 100%. Similarly, 0.5 (<bold>c</bold>) and 1 μg ml<sup>−1</sup> (<bold>d</bold>) CRP-XL-induced fibrinogen binding was measured in the presence or absence of <sup>40</sup>Gap27 (100 μg ml<sup>−1</sup>) in addition to apyrase (4 U ml<sup>−1</sup>) and/or indomethacin (20 μM). The level of fibrinogen binding obtained in the absence of <sup>40</sup>Gap27 (but in the presence of apyrase and/or indomethacin) was taken as 100% to compare the inhibitory levels obtained with <sup>40</sup>Gap27. Data represent mean±s.d. (<italic>n=3</italic>; Student’s <italic>t</italic>-test, *<italic>P</italic><0.05 and **<italic>P</italic><0.01). A, apyrase; C, control; G, <sup>40</sup>Gap27; I, indomethacin.</p></caption><graphic xlink:href="ncomms3564-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Inhibition or deletion of Cx40 or Cx37 does not affect TXB<sub>2</sub> synthesis in platelets.</title><p>The levels of TXB<sub>2</sub> were measured by immunoassay in human PRP following stimulation with 1 μg ml<sup>−1</sup> CRP-XL in the presence or absence of 100 μg ml<sup>−1</sup> of <sup>40</sup>Gap27 or <sup>37,43</sup>Gap27 (<bold>a</bold>). Similarly, TXB<sub>2</sub> levels were measured in <italic>Cx37</italic><sup><italic>−/−</italic></sup> (<bold>b</bold>) and <italic>Cx40</italic><sup><italic>−/−</italic></sup> (<bold>c</bold>) mouse platelets upon stimulation with 1 μg ml<sup>−1</sup> CRP-XL. The levels of TXB<sub>2</sub> obtained in human platelets were shown as concentrations. The levels of TXB<sub>2</sub> obtained with resting platelets in <italic>Cx37</italic><sup><italic>+/+</italic></sup> or <italic>Cx40</italic><sup><italic>+/+</italic></sup> mouse platelets were taken as 100% for comparison with <italic>Cx37-</italic> or <italic>Cx40</italic>-deficient mouse platelets. R, resting platelets. Data represent mean±s.d. (<italic>n=3</italic>; Student’s <italic>t</italic>-test was used for statistical analysis).</p></caption><graphic xlink:href="ncomms3564-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title><sup>37,43</sup>Gap27 does not affect <italic>Cx37></italic><sup><italic>−/−</italic></sup> platelets confirming its selectivity.</title><p>Platelet aggregation performed in the presence or absence of <sup>37,43</sup>Gap27 (100 μg ml<sup>−1</sup>) using washed platelets obtained from <italic>Cx37</italic><sup><italic>+/+</italic></sup> (<bold>a</bold>) and <italic>Cx37</italic><sup><italic>−/−</italic></sup> (<bold>b</bold>) mice was recorded for 180 s following stimulation with CRP-XL (0.5 μg ml<sup>−1</sup>). The level of aggregation obtained in the absence of <sup>37,43</sup>Gap27 was taken as 100%. Data represent mean±s.d. (<italic>n</italic>=3; Student’s <italic>t</italic>-test, *<italic>P</italic><0.05).</p></caption><graphic xlink:href="ncomms3564-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Cx40 regulates platelet function independently from Cx37.</title><p>The levels of fibrinogen binding (<bold>a</bold>) and P-selectin exposure (<bold>b</bold>) in <italic>Cx37</italic><sup><italic>+/+</italic></sup> and <italic>Cx37</italic><sup><italic>−/−</italic></sup> mouse platelets in the presence or absence of <sup>40</sup>Gap27 (100 μg ml<sup>−1</sup>) were measured by flow cytometry using whole blood following stimulation with 1 μg ml<sup>−1</sup> CRP-XL. Similarly, the levels of fibrinogen binding (<bold>c</bold>) and P-selectin exposure (<bold>d</bold>) in <italic>Cx40</italic><sup><italic>+/+</italic></sup> and <italic>Cx40</italic><sup><italic>−/−</italic></sup> mouse platelets in the presence or absence of <sup>37,43</sup>Gap27 (100 μg ml<sup>−1</sup>) were measured following stimulation with 1 μg ml<sup>−1</sup> CRP-XL. The level of fibrinogen binding obtained in the absence of inhibitor was taken 100%. Data represent mean±s.d. (<italic>n=4</italic>; Student’s <italic>t</italic>-test, *<italic>P</italic><0.05 and **<italic>P</italic><0.01).</p></caption><graphic xlink:href="ncomms3564-f7"></graphic></fig><fig id="f8"><label>Figure 8</label><caption><title>Cx40 regulates clot retraction and haemostasis.</title><p>The effect of <sup>40</sup>Gap27 on clot retraction using human PRP was analysed <italic>in vitro</italic> for 90 min (<bold>a</bold>,<bold>b</bold>). The effect of Cx40 deficiency on clot retraction was analysed (<bold>c</bold>,<bold>d</bold>). Data represent mean±s.d. (<italic>n</italic>=4; Student’s <italic>t</italic>-test, *<italic>P</italic><0.05 and **<italic>P</italic><0.01). Deletion of Cx40 or the effect of <sup>40</sup>Gap27 (estimated plasma concentration: 100 μg ml<sup>−1</sup>) on haemostasis in mice was analysed by measuring the bleeding time after tail tip excision. The bleeding time obtained with <italic>Cx40</italic><sup><italic>−/−</italic></sup> mice were compared with <italic>Cx40</italic><sup><italic>+/+</italic></sup> mice (<bold>e</bold>). Similarly, the bleeding time obtained with scrambled peptide- (estimated 100 μg ml<sup>-1</sup>) treated group was compared with <sup>40</sup>Gap27-treated mice (<bold>f</bold>). Data represent mean±s.d. (<italic>n</italic>=5 for <italic>Cx40</italic><sup><italic>+/+</italic></sup>or <italic>Cx40</italic><sup><italic>−/−</italic></sup> mice and <italic>n</italic>=5 mice for scrambled peptide control or <sup>40</sup>Gap27 treated). The significance between control and treated groups, and <italic>P</italic>-values (as shown) were calculated by non-parametric Mann–Whitney test using GraphPad Prism.</p></caption><graphic xlink:href="ncomms3564-f8"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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