Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation
Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretio...
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| Veröffentlicht in: | American Journal of Physiology: Cell Physiology 2014-11, Vol.307 (10), p.C920-C927 |
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| container_title | American Journal of Physiology: Cell Physiology |
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| creator | Münzer, Patrick Schmid, Evi Walker, Britta Fotinos, Anna Chatterjee, Madhumita Rath, Dominik Vogel, Sebastian Hoffmann, Sascha M Metzger, Katja Seizer, Peter Geisler, Tobias Gawaz, Meinrad Borst, Oliver Lang, Florian |
| description | Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation. |
| doi_str_mv | 10.1152/ajpcell.00029.2014 |
| format | Article |
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Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00029.2014</identifier><identifier>PMID: 25231106</identifier><identifier>CODEN: AJPCDD</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Blood platelets ; Calcium ; Female ; Flow cytometry ; Fluorescence ; Kinases ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphotransferases (Alcohol Group Acceptor) - physiology ; Platelet Activation - physiology ; Rodents ; Thrombosis - enzymology ; Thrombosis - pathology ; Thrombosis - prevention & control</subject><ispartof>American Journal of Physiology: Cell Physiology, 2014-11, Vol.307 (10), p.C920-C927</ispartof><rights>Copyright © 2014 the American Physiological Society.</rights><rights>Copyright American Physiological Society Nov 15, 2014</rights><rights>Copyright © 2014 the American Physiological Society 2014 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-9112865c8c5bfcabdb2a60d2b3694fe67d29cc6bac5734b4afbfe4fb3fae102a3</citedby><cites>FETCH-LOGICAL-c430t-9112865c8c5bfcabdb2a60d2b3694fe67d29cc6bac5734b4afbfe4fb3fae102a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25231106$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Münzer, Patrick</creatorcontrib><creatorcontrib>Schmid, Evi</creatorcontrib><creatorcontrib>Walker, Britta</creatorcontrib><creatorcontrib>Fotinos, Anna</creatorcontrib><creatorcontrib>Chatterjee, Madhumita</creatorcontrib><creatorcontrib>Rath, Dominik</creatorcontrib><creatorcontrib>Vogel, Sebastian</creatorcontrib><creatorcontrib>Hoffmann, Sascha M</creatorcontrib><creatorcontrib>Metzger, Katja</creatorcontrib><creatorcontrib>Seizer, Peter</creatorcontrib><creatorcontrib>Geisler, Tobias</creatorcontrib><creatorcontrib>Gawaz, Meinrad</creatorcontrib><creatorcontrib>Borst, Oliver</creatorcontrib><creatorcontrib>Lang, Florian</creatorcontrib><title>Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.</description><subject>Animals</subject><subject>Blood platelets</subject><subject>Calcium</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Fluorescence</subject><subject>Kinases</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - physiology</subject><subject>Platelet Activation - physiology</subject><subject>Rodents</subject><subject>Thrombosis - enzymology</subject><subject>Thrombosis - pathology</subject><subject>Thrombosis - prevention & control</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFv1DAQhS0EotvCH-CALHEph2w9Y8e7uSChCgpSJQ6FG5JlO_Zutokd7KRS_z3e7VLRnkaa983TzDxC3gFbAtR4oXejdX2_ZIxhs0QG4gVZFAErqCV_SRaMS15JEPyEnOa8K5xA2bwmJ1gjB2ByQX7fjNsubGLugqO3XdDZUaDnpXsLH2lwGz11d66_p8lt5l5PLtNxX3o3UW2LVvQYqA4tnbYpDmbO1Mc0HNpvyCuv--zeHusZ-fX1y8_Lb9X1j6vvl5-vKys4m6oGANeytmtbG2-1aQ1qyVo0XDbCO7lqsbFWGm3rFRdGaG-8E95wrx0w1PyMfHrwHWczuNa6MCXdqzF1g073KupOPVVCt1WbeKcEco4Si8H50SDFP7PLkxq6vP-tDi7OWYHElWzWUDcF_fAM3cU5hXLegQJRCwaFwgfKpphzcv5xGWBqH546hqcO4al9eGXo_f9nPI78S4v_Bazdmag</recordid><startdate>20141115</startdate><enddate>20141115</enddate><creator>Münzer, Patrick</creator><creator>Schmid, Evi</creator><creator>Walker, Britta</creator><creator>Fotinos, Anna</creator><creator>Chatterjee, Madhumita</creator><creator>Rath, Dominik</creator><creator>Vogel, Sebastian</creator><creator>Hoffmann, Sascha M</creator><creator>Metzger, Katja</creator><creator>Seizer, Peter</creator><creator>Geisler, Tobias</creator><creator>Gawaz, Meinrad</creator><creator>Borst, Oliver</creator><creator>Lang, Florian</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141115</creationdate><title>Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation</title><author>Münzer, Patrick ; Schmid, Evi ; Walker, Britta ; Fotinos, Anna ; Chatterjee, Madhumita ; Rath, Dominik ; Vogel, Sebastian ; Hoffmann, Sascha M ; Metzger, Katja ; Seizer, Peter ; Geisler, Tobias ; Gawaz, Meinrad ; Borst, Oliver ; Lang, Florian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-9112865c8c5bfcabdb2a60d2b3694fe67d29cc6bac5734b4afbfe4fb3fae102a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Blood platelets</topic><topic>Calcium</topic><topic>Female</topic><topic>Flow cytometry</topic><topic>Fluorescence</topic><topic>Kinases</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - physiology</topic><topic>Platelet Activation - physiology</topic><topic>Rodents</topic><topic>Thrombosis - enzymology</topic><topic>Thrombosis - pathology</topic><topic>Thrombosis - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Münzer, Patrick</creatorcontrib><creatorcontrib>Schmid, Evi</creatorcontrib><creatorcontrib>Walker, Britta</creatorcontrib><creatorcontrib>Fotinos, Anna</creatorcontrib><creatorcontrib>Chatterjee, Madhumita</creatorcontrib><creatorcontrib>Rath, Dominik</creatorcontrib><creatorcontrib>Vogel, Sebastian</creatorcontrib><creatorcontrib>Hoffmann, Sascha M</creatorcontrib><creatorcontrib>Metzger, Katja</creatorcontrib><creatorcontrib>Seizer, Peter</creatorcontrib><creatorcontrib>Geisler, Tobias</creatorcontrib><creatorcontrib>Gawaz, Meinrad</creatorcontrib><creatorcontrib>Borst, Oliver</creatorcontrib><creatorcontrib>Lang, Florian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Münzer, Patrick</au><au>Schmid, Evi</au><au>Walker, Britta</au><au>Fotinos, Anna</au><au>Chatterjee, Madhumita</au><au>Rath, Dominik</au><au>Vogel, Sebastian</au><au>Hoffmann, Sascha M</au><au>Metzger, Katja</au><au>Seizer, Peter</au><au>Geisler, Tobias</au><au>Gawaz, Meinrad</au><au>Borst, Oliver</au><au>Lang, Florian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2014-11-15</date><risdate>2014</risdate><volume>307</volume><issue>10</issue><spage>C920</spage><epage>C927</epage><pages>C920-C927</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><coden>AJPCDD</coden><abstract>Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>25231106</pmid><doi>10.1152/ajpcell.00029.2014</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blood platelets Calcium Female Flow cytometry Fluorescence Kinases Male Mice Mice, Inbred C57BL Mice, Knockout Phosphotransferases (Alcohol Group Acceptor) - physiology Platelet Activation - physiology Rodents Thrombosis - enzymology Thrombosis - pathology Thrombosis - prevention & control |
| title | Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation |
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