Compression force sensing regulates integrin α IIb β 3 adhesive function on diabetic platelets
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force ac...
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| Veröffentlicht in: | Nature communications 2018-03, Vol.9 (1), p.1087 |
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| creator | Ju, Lining McFadyen, James D Al-Daher, Saheb Alwis, Imala Chen, Yunfeng Tønnesen, Lotte L Maiocchi, Sophie Coulter, Brianna Calkin, Anna C Felner, Eric I Cohen, Neale Yuan, Yuping Schoenwaelder, Simone M Cooper, Mark E Zhu, Cheng Jackson, Shaun P |
| description | Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin α
β
on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to α
β
adhesive function that leads to a distinct prothrombotic phenotype in diabetes. |
| doi_str_mv | 10.1038/s41467-018-03430-6 |
| format | Article |
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β
on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to α
β
adhesive function that leads to a distinct prothrombotic phenotype in diabetes.</description><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-018-03430-6</identifier><identifier>PMID: 29540687</identifier><language>eng</language><publisher>England</publisher><subject>Adult ; Animals ; Aspirin - pharmacology ; Blood Platelets - drug effects ; Blood Platelets - metabolism ; Clopidogrel ; Diabetes Mellitus, Type 1 - metabolism ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Platelet Adhesiveness - drug effects ; Platelet Adhesiveness - physiology ; Platelet Aggregation - drug effects ; Platelet Aggregation - physiology ; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism ; Thrombosis - metabolism ; Ticlopidine - analogs & derivatives ; Ticlopidine - pharmacology</subject><ispartof>Nature communications, 2018-03, Vol.9 (1), p.1087</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-1718-565X ; 0000-0001-7618-107X ; 0000-0002-0492-9234 ; 0000-0002-7591-0864 ; 0000-0003-0465-5840</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29540687$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ju, Lining</creatorcontrib><creatorcontrib>McFadyen, James D</creatorcontrib><creatorcontrib>Al-Daher, Saheb</creatorcontrib><creatorcontrib>Alwis, Imala</creatorcontrib><creatorcontrib>Chen, Yunfeng</creatorcontrib><creatorcontrib>Tønnesen, Lotte L</creatorcontrib><creatorcontrib>Maiocchi, Sophie</creatorcontrib><creatorcontrib>Coulter, Brianna</creatorcontrib><creatorcontrib>Calkin, Anna C</creatorcontrib><creatorcontrib>Felner, Eric I</creatorcontrib><creatorcontrib>Cohen, Neale</creatorcontrib><creatorcontrib>Yuan, Yuping</creatorcontrib><creatorcontrib>Schoenwaelder, Simone M</creatorcontrib><creatorcontrib>Cooper, Mark E</creatorcontrib><creatorcontrib>Zhu, Cheng</creatorcontrib><creatorcontrib>Jackson, Shaun P</creatorcontrib><title>Compression force sensing regulates integrin α IIb β 3 adhesive function on diabetic platelets</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><description>Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin α
β
on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to α
β
adhesive function that leads to a distinct prothrombotic phenotype in diabetes.</description><subject>Adult</subject><subject>Animals</subject><subject>Aspirin - pharmacology</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - metabolism</subject><subject>Clopidogrel</subject><subject>Diabetes Mellitus, Type 1 - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Platelet Adhesiveness - drug effects</subject><subject>Platelet Adhesiveness - physiology</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation - physiology</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</subject><subject>Thrombosis - metabolism</subject><subject>Ticlopidine - analogs & derivatives</subject><subject>Ticlopidine - pharmacology</subject><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjkFqwzAUREWhJKbJBbIo_wJqJUuxnXVIaPbdJ7L97arYstGXAzlWchCfqTa06w4Ds3kPhrGNFG9SqOydtNRJyoXMuFBaCZ48sSgWWnKZxmrJ1kTfYorayUzrBVvGu60WSZZG7LLv2t4jke0cVJ0vEAgdWVeDx3poTEAC6wLW3joY73A65TA-QIEpv5DsFaEaXBFmfWppTY7BFtDPZoOBVuy5Mg3h-ndf2Ovx8Ln_4P2Qt1iee29b42_nv0vqX-AHWF9JxQ</recordid><startdate>20180314</startdate><enddate>20180314</enddate><creator>Ju, Lining</creator><creator>McFadyen, James D</creator><creator>Al-Daher, Saheb</creator><creator>Alwis, Imala</creator><creator>Chen, Yunfeng</creator><creator>Tønnesen, Lotte L</creator><creator>Maiocchi, Sophie</creator><creator>Coulter, Brianna</creator><creator>Calkin, Anna C</creator><creator>Felner, Eric I</creator><creator>Cohen, Neale</creator><creator>Yuan, Yuping</creator><creator>Schoenwaelder, Simone M</creator><creator>Cooper, Mark E</creator><creator>Zhu, Cheng</creator><creator>Jackson, Shaun P</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-1718-565X</orcidid><orcidid>https://orcid.org/0000-0001-7618-107X</orcidid><orcidid>https://orcid.org/0000-0002-0492-9234</orcidid><orcidid>https://orcid.org/0000-0002-7591-0864</orcidid><orcidid>https://orcid.org/0000-0003-0465-5840</orcidid></search><sort><creationdate>20180314</creationdate><title>Compression force sensing regulates integrin α IIb β 3 adhesive function on diabetic platelets</title><author>Ju, Lining ; McFadyen, James D ; Al-Daher, Saheb ; Alwis, Imala ; Chen, Yunfeng ; Tønnesen, Lotte L ; Maiocchi, Sophie ; Coulter, Brianna ; Calkin, Anna C ; Felner, Eric I ; Cohen, Neale ; Yuan, Yuping ; Schoenwaelder, Simone M ; Cooper, Mark E ; Zhu, Cheng ; Jackson, Shaun P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_295406873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Animals</topic><topic>Aspirin - pharmacology</topic><topic>Blood Platelets - drug effects</topic><topic>Blood Platelets - metabolism</topic><topic>Clopidogrel</topic><topic>Diabetes Mellitus, Type 1 - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Platelet Adhesiveness - drug effects</topic><topic>Platelet Adhesiveness - physiology</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation - physiology</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</topic><topic>Thrombosis - metabolism</topic><topic>Ticlopidine - analogs & derivatives</topic><topic>Ticlopidine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ju, Lining</creatorcontrib><creatorcontrib>McFadyen, James D</creatorcontrib><creatorcontrib>Al-Daher, Saheb</creatorcontrib><creatorcontrib>Alwis, Imala</creatorcontrib><creatorcontrib>Chen, Yunfeng</creatorcontrib><creatorcontrib>Tønnesen, Lotte L</creatorcontrib><creatorcontrib>Maiocchi, Sophie</creatorcontrib><creatorcontrib>Coulter, Brianna</creatorcontrib><creatorcontrib>Calkin, Anna C</creatorcontrib><creatorcontrib>Felner, Eric I</creatorcontrib><creatorcontrib>Cohen, Neale</creatorcontrib><creatorcontrib>Yuan, Yuping</creatorcontrib><creatorcontrib>Schoenwaelder, Simone M</creatorcontrib><creatorcontrib>Cooper, Mark E</creatorcontrib><creatorcontrib>Zhu, Cheng</creatorcontrib><creatorcontrib>Jackson, Shaun P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ju, Lining</au><au>McFadyen, James D</au><au>Al-Daher, Saheb</au><au>Alwis, Imala</au><au>Chen, Yunfeng</au><au>Tønnesen, Lotte L</au><au>Maiocchi, Sophie</au><au>Coulter, Brianna</au><au>Calkin, Anna C</au><au>Felner, Eric I</au><au>Cohen, Neale</au><au>Yuan, Yuping</au><au>Schoenwaelder, Simone M</au><au>Cooper, Mark E</au><au>Zhu, Cheng</au><au>Jackson, Shaun P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Compression force sensing regulates integrin α IIb β 3 adhesive function on diabetic platelets</atitle><jtitle>Nature communications</jtitle><addtitle>Nat Commun</addtitle><date>2018-03-14</date><risdate>2018</risdate><volume>9</volume><issue>1</issue><spage>1087</spage><pages>1087-</pages><eissn>2041-1723</eissn><abstract>Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin α
β
on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to α
β
adhesive function that leads to a distinct prothrombotic phenotype in diabetes.</abstract><cop>England</cop><pmid>29540687</pmid><doi>10.1038/s41467-018-03430-6</doi><orcidid>https://orcid.org/0000-0002-1718-565X</orcidid><orcidid>https://orcid.org/0000-0001-7618-107X</orcidid><orcidid>https://orcid.org/0000-0002-0492-9234</orcidid><orcidid>https://orcid.org/0000-0002-7591-0864</orcidid><orcidid>https://orcid.org/0000-0003-0465-5840</orcidid></addata></record> |
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| subjects | Adult Animals Aspirin - pharmacology Blood Platelets - drug effects Blood Platelets - metabolism Clopidogrel Diabetes Mellitus, Type 1 - metabolism Female Humans Male Mice Mice, Inbred C57BL Middle Aged Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Platelet Adhesiveness - drug effects Platelet Adhesiveness - physiology Platelet Aggregation - drug effects Platelet Aggregation - physiology Platelet Glycoprotein GPIIb-IIIa Complex - metabolism Thrombosis - metabolism Ticlopidine - analogs & derivatives Ticlopidine - pharmacology |
| title | Compression force sensing regulates integrin α IIb β 3 adhesive function on diabetic platelets |
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