Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation
Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP...
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| description | Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p |
| doi_str_mv | 10.1371/journal.pone.0038455 |
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However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2)Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P(2)Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2)Y and PI3K blockade (p<0.05). Combined blockade of P(2)Y(12), P(2)Y(1) and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0038455</identifier><identifier>PMID: 22701645</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Acute coronary syndromes ; Adenosine diphosphate ; Adenosine Diphosphate - analogs & derivatives ; Adenosine Diphosphate - pharmacology ; Analysis of Variance ; Anesthesiology ; Biology ; Blood ; Blood circulation ; Blood platelets ; Cardiac Surgical Procedures - methods ; Cell activation ; Class I Phosphatidylinositol 3-Kinases ; Complications ; Cytometry ; Drug dosages ; Enzyme-Linked Immunosorbent Assay ; Extracorporeal Circulation - adverse effects ; Extracorporeal Circulation - methods ; Flow Cytometry ; Heart diseases ; Heart surgery ; Humans ; Hypothermia ; Hypothermia, Induced - adverse effects ; Hypothermia, Induced - methods ; In Vitro Techniques ; Inhibition ; Intensive care ; Ischemia ; Kinases ; Leukocytes ; Leukocytes (granulocytic) ; Leukocytes - drug effects ; Leukocytes - physiology ; Ligands ; Mac1 protein ; Medicine ; Microparticles ; Models, Biological ; Morpholines - pharmacology ; P-selectin ; P-Selectin - metabolism ; Pharmacology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Platelet Activation - drug effects ; Platelet Activation - physiology ; Platelet Count ; Platelets ; Propylene ; Propylene glycol ; Purinergic P2 Receptor Antagonists - pharmacology ; Pyrimidinones - pharmacology ; Receptors ; Surgery ; Therapeutic applications ; Thromboembolism ; Von Willebrand factor</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e38455-e38455</ispartof><rights>2012 Krajewski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Krajewski et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-e3ab5a69605b841825fb9305d87297382ab1637ff2dce6fd64b8806a1278de53</citedby><cites>FETCH-LOGICAL-c526t-e3ab5a69605b841825fb9305d87297382ab1637ff2dce6fd64b8806a1278de53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368839/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368839/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22701645$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Schulz, Christian</contributor><creatorcontrib>Krajewski, Stefanie</creatorcontrib><creatorcontrib>Kurz, Julia</creatorcontrib><creatorcontrib>Geisler, Tobias</creatorcontrib><creatorcontrib>Peter, Karlheinz</creatorcontrib><creatorcontrib>Wendel, Hans Peter</creatorcontrib><creatorcontrib>Straub, Andreas</creatorcontrib><title>Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2)Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P(2)Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2)Y and PI3K blockade (p<0.05). Combined blockade of P(2)Y(12), P(2)Y(1) and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Acute coronary syndromes</subject><subject>Adenosine diphosphate</subject><subject>Adenosine Diphosphate - analogs & derivatives</subject><subject>Adenosine Diphosphate - pharmacology</subject><subject>Analysis of Variance</subject><subject>Anesthesiology</subject><subject>Biology</subject><subject>Blood</subject><subject>Blood circulation</subject><subject>Blood platelets</subject><subject>Cardiac Surgical Procedures - methods</subject><subject>Cell activation</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Complications</subject><subject>Cytometry</subject><subject>Drug dosages</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Extracorporeal Circulation - adverse effects</subject><subject>Extracorporeal Circulation - methods</subject><subject>Flow Cytometry</subject><subject>Heart diseases</subject><subject>Heart surgery</subject><subject>Humans</subject><subject>Hypothermia</subject><subject>Hypothermia, Induced - adverse effects</subject><subject>Hypothermia, Induced - methods</subject><subject>In Vitro Techniques</subject><subject>Inhibition</subject><subject>Intensive care</subject><subject>Ischemia</subject><subject>Kinases</subject><subject>Leukocytes</subject><subject>Leukocytes (granulocytic)</subject><subject>Leukocytes - drug effects</subject><subject>Leukocytes - physiology</subject><subject>Ligands</subject><subject>Mac1 protein</subject><subject>Medicine</subject><subject>Microparticles</subject><subject>Models, Biological</subject><subject>Morpholines - pharmacology</subject><subject>P-selectin</subject><subject>P-Selectin - metabolism</subject><subject>Pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Platelet Activation - drug effects</subject><subject>Platelet Activation - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krajewski, Stefanie</au><au>Kurz, Julia</au><au>Geisler, Tobias</au><au>Peter, Karlheinz</au><au>Wendel, Hans Peter</au><au>Straub, Andreas</au><au>Schulz, Christian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-06</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e38455</spage><epage>e38455</epage><pages>e38455-e38455</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2)Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P(2)Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2)Y and PI3K blockade (p<0.05). Combined blockade of P(2)Y(12), P(2)Y(1) and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22701645</pmid><doi>10.1371/journal.pone.0038455</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e38455-e38455 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1330880338 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase Acute coronary syndromes Adenosine diphosphate Adenosine Diphosphate - analogs & derivatives Adenosine Diphosphate - pharmacology Analysis of Variance Anesthesiology Biology Blood Blood circulation Blood platelets Cardiac Surgical Procedures - methods Cell activation Class I Phosphatidylinositol 3-Kinases Complications Cytometry Drug dosages Enzyme-Linked Immunosorbent Assay Extracorporeal Circulation - adverse effects Extracorporeal Circulation - methods Flow Cytometry Heart diseases Heart surgery Humans Hypothermia Hypothermia, Induced - adverse effects Hypothermia, Induced - methods In Vitro Techniques Inhibition Intensive care Ischemia Kinases Leukocytes Leukocytes (granulocytic) Leukocytes - drug effects Leukocytes - physiology Ligands Mac1 protein Medicine Microparticles Models, Biological Morpholines - pharmacology P-selectin P-Selectin - metabolism Pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Platelet Activation - drug effects Platelet Activation - physiology Platelet Count Platelets Propylene Propylene glycol Purinergic P2 Receptor Antagonists - pharmacology Pyrimidinones - pharmacology Receptors Surgery Therapeutic applications Thromboembolism Von Willebrand factor |
| title | Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation |
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