Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury
Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα i proteins in mice has both protective and deleterious effects on myocardial...
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| creator | Köhler, David Leiss, Veronika Beichert, Lukas Killinger, Simon Grothe, Daniela Kushwaha, Ragini Schröter, Agnes Roslan, Anna Eggstein, Claudia Focken, Jule Granja, Tiago Devanathan, Vasudharani Schittek, Birgit Lukowski, Robert Weigelin, Bettina Rosenberger, Peter Nürnberg, Bernd Beer-Hammer, Sandra |
| description | Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα
i
proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα
i2
proteins in resident cardiac
vs
circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα
i2
in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR)
Gnai2
−/−
→ wt
vs
44.0% wt → wt;
p
|
| doi_str_mv | 10.1007/s00395-024-01057-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11461587</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3062527635</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-f8f4994c9888c5f5fde2234d6eedb003da6a728abe7ff178b73c4023ffa722503</originalsourceid><addsrcrecordid>eNp9kctO3DAYha0KVC7tC3RRRWLTTYov8WVWFRoVqITEArq2PM7vGY8SO7UTxDxWX6TPhGEotwUrW_6_c-zjg9AXgr8TjOVxxpjNeI1pU2OCuaxvP6B90jBeE4XZzov9HjrIeY0xaYQgH9EeU4qQhpJ9dHVt0hJGH5bV2b-_nlY-VAGmMcVh5btcDSmOYMdcuRT7qt9Ea1LrTVf5bFfQe1MlGCC5KfsYing9pc0ntOtMl-Hz43qIfp_-vJ6f1xeXZ7_mJxe1ZVyMtVOumc0aO1NKWe64a4FS1rQCoF2UaK0RRlJlFiCdI1ItJLMNpsy5ckw5Zofox9Z3mBY9tBbCmEynh-R7kzY6Gq9fT4Jf6WW80SW7IFzJ4vDt0SHFPxPkUfclF3SdCRCnrBkWlFMpGC_o0Rt0HacUSj7N7v9SCsxIoeiWsinmnMA9vYZgfV-a3pamS2n6oTR9W0RfX-Z4kvxvqQBsC-QyCktIz3e_Y3sHqTilWg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3114276031</pqid></control><display><type>article</type><title>Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Köhler, David ; Leiss, Veronika ; Beichert, Lukas ; Killinger, Simon ; Grothe, Daniela ; Kushwaha, Ragini ; Schröter, Agnes ; Roslan, Anna ; Eggstein, Claudia ; Focken, Jule ; Granja, Tiago ; Devanathan, Vasudharani ; Schittek, Birgit ; Lukowski, Robert ; Weigelin, Bettina ; Rosenberger, Peter ; Nürnberg, Bernd ; Beer-Hammer, Sandra</creator><creatorcontrib>Köhler, David ; Leiss, Veronika ; Beichert, Lukas ; Killinger, Simon ; Grothe, Daniela ; Kushwaha, Ragini ; Schröter, Agnes ; Roslan, Anna ; Eggstein, Claudia ; Focken, Jule ; Granja, Tiago ; Devanathan, Vasudharani ; Schittek, Birgit ; Lukowski, Robert ; Weigelin, Bettina ; Rosenberger, Peter ; Nürnberg, Bernd ; Beer-Hammer, Sandra</creatorcontrib><description><![CDATA[Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα
i
proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα
i2
proteins in resident cardiac
vs
circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα
i2
in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR)
Gnai2
−/−
→ wt
vs
44.0% wt → wt;
p
< 0.001) whereas the absence of Gα
i2
in non-hematopoietic cells increased the infarct damage (66.5% wt →
Gnai2
−/−
vs
44.0% wt → wt;
p
< 0.001). Previously we have reported the impact of platelet Gα
i2
for mIRI. Here, we show that infarct size was substantially reduced when Gα
i2
signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9%
Gnai2
fl/fl
LysM-Cre
+
/tg
vs
42.0%
Gnai2
fl/fl
;
p
< 0.01) or selectively blocked with specific antibodies directed against Gα
i2
(AAR: 19.0% (anti-Gα
i2
)
vs
49.0% (IgG);
p
< 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (
Gnai2
fl/fl
; LysM-Cre
+
/tg
)
vs
31 (
Gnai2
fl/fl
);
p
< 0.001) and in anti-Gα
i2
antibody-treated (PNCs: 9 (anti-Gα
i2
)
vs
33 (IgG);
p
< 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα
i2
antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα
i2
antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG)
vs
13,225 (anti-Gα
i2
) neutrophils;
p
< 0.001), collectively suggesting that a therapeutic concept of functional Gα
i2
inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.]]></description><identifier>ISSN: 1435-1803</identifier><identifier>ISSN: 0300-8428</identifier><identifier>EISSN: 1435-1803</identifier><identifier>DOI: 10.1007/s00395-024-01057-x</identifier><identifier>PMID: 38811421</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Ablation ; Animals ; Antibodies ; Blood cells ; Blood circulation ; Blood vessels ; Bone marrow ; Cardiology ; Cell size ; Chimeras ; Cre recombinase ; Damage ; Disease Models, Animal ; Genetic modification ; GTP-Binding Protein alpha Subunit, Gi2 - genetics ; GTP-Binding Protein alpha Subunit, Gi2 - metabolism ; Heart rate ; Hematopoietic stem cells ; Humans ; Immune system ; Immunoglobulin G ; Injury analysis ; Ischemia ; Leukocyte migration ; Leukocytes (neutrophilic) ; Macrophages ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial infarction ; Myocardial ischemia ; Myocardial Reperfusion Injury - genetics ; Myocardial Reperfusion Injury - immunology ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - pathology ; Myocardial Reperfusion Injury - prevention & control ; Neutrophils ; Neutrophils - immunology ; Neutrophils - metabolism ; Original Contribution ; Platelets ; Proteins ; Reperfusion ; Signal Transduction ; Thrombolysis</subject><ispartof>Basic research in cardiology, 2024-10, Vol.119 (5), p.717-732</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c356t-f8f4994c9888c5f5fde2234d6eedb003da6a728abe7ff178b73c4023ffa722503</cites><orcidid>0000-0001-6049-0257</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00395-024-01057-x$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00395-024-01057-x$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38811421$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Köhler, David</creatorcontrib><creatorcontrib>Leiss, Veronika</creatorcontrib><creatorcontrib>Beichert, Lukas</creatorcontrib><creatorcontrib>Killinger, Simon</creatorcontrib><creatorcontrib>Grothe, Daniela</creatorcontrib><creatorcontrib>Kushwaha, Ragini</creatorcontrib><creatorcontrib>Schröter, Agnes</creatorcontrib><creatorcontrib>Roslan, Anna</creatorcontrib><creatorcontrib>Eggstein, Claudia</creatorcontrib><creatorcontrib>Focken, Jule</creatorcontrib><creatorcontrib>Granja, Tiago</creatorcontrib><creatorcontrib>Devanathan, Vasudharani</creatorcontrib><creatorcontrib>Schittek, Birgit</creatorcontrib><creatorcontrib>Lukowski, Robert</creatorcontrib><creatorcontrib>Weigelin, Bettina</creatorcontrib><creatorcontrib>Rosenberger, Peter</creatorcontrib><creatorcontrib>Nürnberg, Bernd</creatorcontrib><creatorcontrib>Beer-Hammer, Sandra</creatorcontrib><title>Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury</title><title>Basic research in cardiology</title><addtitle>Basic Res Cardiol</addtitle><addtitle>Basic Res Cardiol</addtitle><description><![CDATA[Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα
i
proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα
i2
proteins in resident cardiac
vs
circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα
i2
in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR)
Gnai2
−/−
→ wt
vs
44.0% wt → wt;
p
< 0.001) whereas the absence of Gα
i2
in non-hematopoietic cells increased the infarct damage (66.5% wt →
Gnai2
−/−
vs
44.0% wt → wt;
p
< 0.001). Previously we have reported the impact of platelet Gα
i2
for mIRI. Here, we show that infarct size was substantially reduced when Gα
i2
signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9%
Gnai2
fl/fl
LysM-Cre
+
/tg
vs
42.0%
Gnai2
fl/fl
;
p
< 0.01) or selectively blocked with specific antibodies directed against Gα
i2
(AAR: 19.0% (anti-Gα
i2
)
vs
49.0% (IgG);
p
< 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (
Gnai2
fl/fl
; LysM-Cre
+
/tg
)
vs
31 (
Gnai2
fl/fl
);
p
< 0.001) and in anti-Gα
i2
antibody-treated (PNCs: 9 (anti-Gα
i2
)
vs
33 (IgG);
p
< 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα
i2
antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα
i2
antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG)
vs
13,225 (anti-Gα
i2
) neutrophils;
p
< 0.001), collectively suggesting that a therapeutic concept of functional Gα
i2
inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.]]></description><subject>Ablation</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Blood cells</subject><subject>Blood circulation</subject><subject>Blood vessels</subject><subject>Bone marrow</subject><subject>Cardiology</subject><subject>Cell size</subject><subject>Chimeras</subject><subject>Cre recombinase</subject><subject>Damage</subject><subject>Disease Models, Animal</subject><subject>Genetic modification</subject><subject>GTP-Binding Protein alpha Subunit, Gi2 - genetics</subject><subject>GTP-Binding Protein alpha Subunit, Gi2 - metabolism</subject><subject>Heart rate</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunoglobulin G</subject><subject>Injury analysis</subject><subject>Ischemia</subject><subject>Leukocyte migration</subject><subject>Leukocytes (neutrophilic)</subject><subject>Macrophages</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocardial infarction</subject><subject>Myocardial ischemia</subject><subject>Myocardial Reperfusion Injury - genetics</subject><subject>Myocardial Reperfusion Injury - immunology</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Myocardial Reperfusion Injury - pathology</subject><subject>Myocardial Reperfusion Injury - prevention & control</subject><subject>Neutrophils</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - metabolism</subject><subject>Original Contribution</subject><subject>Platelets</subject><subject>Proteins</subject><subject>Reperfusion</subject><subject>Signal Transduction</subject><subject>Thrombolysis</subject><issn>1435-1803</issn><issn>0300-8428</issn><issn>1435-1803</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kctO3DAYha0KVC7tC3RRRWLTTYov8WVWFRoVqITEArq2PM7vGY8SO7UTxDxWX6TPhGEotwUrW_6_c-zjg9AXgr8TjOVxxpjNeI1pU2OCuaxvP6B90jBeE4XZzov9HjrIeY0xaYQgH9EeU4qQhpJ9dHVt0hJGH5bV2b-_nlY-VAGmMcVh5btcDSmOYMdcuRT7qt9Ea1LrTVf5bFfQe1MlGCC5KfsYing9pc0ntOtMl-Hz43qIfp_-vJ6f1xeXZ7_mJxe1ZVyMtVOumc0aO1NKWe64a4FS1rQCoF2UaK0RRlJlFiCdI1ItJLMNpsy5ckw5Zofox9Z3mBY9tBbCmEynh-R7kzY6Gq9fT4Jf6WW80SW7IFzJ4vDt0SHFPxPkUfclF3SdCRCnrBkWlFMpGC_o0Rt0HacUSj7N7v9SCsxIoeiWsinmnMA9vYZgfV-a3pamS2n6oTR9W0RfX-Z4kvxvqQBsC-QyCktIz3e_Y3sHqTilWg</recordid><startdate>20241001</startdate><enddate>20241001</enddate><creator>Köhler, David</creator><creator>Leiss, Veronika</creator><creator>Beichert, Lukas</creator><creator>Killinger, Simon</creator><creator>Grothe, Daniela</creator><creator>Kushwaha, Ragini</creator><creator>Schröter, Agnes</creator><creator>Roslan, Anna</creator><creator>Eggstein, Claudia</creator><creator>Focken, Jule</creator><creator>Granja, Tiago</creator><creator>Devanathan, Vasudharani</creator><creator>Schittek, Birgit</creator><creator>Lukowski, Robert</creator><creator>Weigelin, Bettina</creator><creator>Rosenberger, Peter</creator><creator>Nürnberg, Bernd</creator><creator>Beer-Hammer, Sandra</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><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>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>M7Z</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6049-0257</orcidid></search><sort><creationdate>20241001</creationdate><title>Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury</title><author>Köhler, David ; Leiss, Veronika ; Beichert, Lukas ; Killinger, Simon ; Grothe, Daniela ; Kushwaha, Ragini ; Schröter, Agnes ; Roslan, Anna ; Eggstein, Claudia ; Focken, Jule ; Granja, Tiago ; Devanathan, Vasudharani ; Schittek, Birgit ; Lukowski, Robert ; Weigelin, Bettina ; Rosenberger, Peter ; Nürnberg, Bernd ; Beer-Hammer, Sandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-f8f4994c9888c5f5fde2234d6eedb003da6a728abe7ff178b73c4023ffa722503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Ablation</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Blood cells</topic><topic>Blood circulation</topic><topic>Blood vessels</topic><topic>Bone marrow</topic><topic>Cardiology</topic><topic>Cell size</topic><topic>Chimeras</topic><topic>Cre recombinase</topic><topic>Damage</topic><topic>Disease Models, Animal</topic><topic>Genetic modification</topic><topic>GTP-Binding Protein alpha Subunit, Gi2 - genetics</topic><topic>GTP-Binding Protein alpha Subunit, Gi2 - metabolism</topic><topic>Heart rate</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunoglobulin G</topic><topic>Injury analysis</topic><topic>Ischemia</topic><topic>Leukocyte migration</topic><topic>Leukocytes (neutrophilic)</topic><topic>Macrophages</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocardial infarction</topic><topic>Myocardial ischemia</topic><topic>Myocardial Reperfusion Injury - genetics</topic><topic>Myocardial Reperfusion Injury - immunology</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Myocardial Reperfusion Injury - pathology</topic><topic>Myocardial Reperfusion Injury - prevention & control</topic><topic>Neutrophils</topic><topic>Neutrophils - immunology</topic><topic>Neutrophils - metabolism</topic><topic>Original Contribution</topic><topic>Platelets</topic><topic>Proteins</topic><topic>Reperfusion</topic><topic>Signal Transduction</topic><topic>Thrombolysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Köhler, David</creatorcontrib><creatorcontrib>Leiss, Veronika</creatorcontrib><creatorcontrib>Beichert, Lukas</creatorcontrib><creatorcontrib>Killinger, Simon</creatorcontrib><creatorcontrib>Grothe, Daniela</creatorcontrib><creatorcontrib>Kushwaha, Ragini</creatorcontrib><creatorcontrib>Schröter, Agnes</creatorcontrib><creatorcontrib>Roslan, Anna</creatorcontrib><creatorcontrib>Eggstein, Claudia</creatorcontrib><creatorcontrib>Focken, Jule</creatorcontrib><creatorcontrib>Granja, Tiago</creatorcontrib><creatorcontrib>Devanathan, Vasudharani</creatorcontrib><creatorcontrib>Schittek, Birgit</creatorcontrib><creatorcontrib>Lukowski, Robert</creatorcontrib><creatorcontrib>Weigelin, Bettina</creatorcontrib><creatorcontrib>Rosenberger, Peter</creatorcontrib><creatorcontrib>Nürnberg, Bernd</creatorcontrib><creatorcontrib>Beer-Hammer, Sandra</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Basic research in cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Köhler, David</au><au>Leiss, Veronika</au><au>Beichert, Lukas</au><au>Killinger, Simon</au><au>Grothe, Daniela</au><au>Kushwaha, Ragini</au><au>Schröter, Agnes</au><au>Roslan, Anna</au><au>Eggstein, Claudia</au><au>Focken, Jule</au><au>Granja, Tiago</au><au>Devanathan, Vasudharani</au><au>Schittek, Birgit</au><au>Lukowski, Robert</au><au>Weigelin, Bettina</au><au>Rosenberger, Peter</au><au>Nürnberg, Bernd</au><au>Beer-Hammer, Sandra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury</atitle><jtitle>Basic research in cardiology</jtitle><stitle>Basic Res Cardiol</stitle><addtitle>Basic Res Cardiol</addtitle><date>2024-10-01</date><risdate>2024</risdate><volume>119</volume><issue>5</issue><spage>717</spage><epage>732</epage><pages>717-732</pages><issn>1435-1803</issn><issn>0300-8428</issn><eissn>1435-1803</eissn><abstract><![CDATA[Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα
i
proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα
i2
proteins in resident cardiac
vs
circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα
i2
in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR)
Gnai2
−/−
→ wt
vs
44.0% wt → wt;
p
< 0.001) whereas the absence of Gα
i2
in non-hematopoietic cells increased the infarct damage (66.5% wt →
Gnai2
−/−
vs
44.0% wt → wt;
p
< 0.001). Previously we have reported the impact of platelet Gα
i2
for mIRI. Here, we show that infarct size was substantially reduced when Gα
i2
signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9%
Gnai2
fl/fl
LysM-Cre
+
/tg
vs
42.0%
Gnai2
fl/fl
;
p
< 0.01) or selectively blocked with specific antibodies directed against Gα
i2
(AAR: 19.0% (anti-Gα
i2
)
vs
49.0% (IgG);
p
< 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (
Gnai2
fl/fl
; LysM-Cre
+
/tg
)
vs
31 (
Gnai2
fl/fl
);
p
< 0.001) and in anti-Gα
i2
antibody-treated (PNCs: 9 (anti-Gα
i2
)
vs
33 (IgG);
p
< 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα
i2
antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα
i2
antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG)
vs
13,225 (anti-Gα
i2
) neutrophils;
p
< 0.001), collectively suggesting that a therapeutic concept of functional Gα
i2
inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.]]></abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>38811421</pmid><doi>10.1007/s00395-024-01057-x</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-6049-0257</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1435-1803 |
| ispartof | Basic research in cardiology, 2024-10, Vol.119 (5), p.717-732 |
| issn | 1435-1803 0300-8428 1435-1803 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11461587 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Ablation Animals Antibodies Blood cells Blood circulation Blood vessels Bone marrow Cardiology Cell size Chimeras Cre recombinase Damage Disease Models, Animal Genetic modification GTP-Binding Protein alpha Subunit, Gi2 - genetics GTP-Binding Protein alpha Subunit, Gi2 - metabolism Heart rate Hematopoietic stem cells Humans Immune system Immunoglobulin G Injury analysis Ischemia Leukocyte migration Leukocytes (neutrophilic) Macrophages Male Medicine Medicine & Public Health Mice Mice, Inbred C57BL Mice, Knockout Myocardial infarction Myocardial ischemia Myocardial Reperfusion Injury - genetics Myocardial Reperfusion Injury - immunology Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - prevention & control Neutrophils Neutrophils - immunology Neutrophils - metabolism Original Contribution Platelets Proteins Reperfusion Signal Transduction Thrombolysis |
| title | Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T02%3A45%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20G%CE%B1i2%20in%20neutrophils%20protects%20from%20myocardial%20ischemia%20reperfusion%20injury&rft.jtitle=Basic%20research%20in%20cardiology&rft.au=K%C3%B6hler,%20David&rft.date=2024-10-01&rft.volume=119&rft.issue=5&rft.spage=717&rft.epage=732&rft.pages=717-732&rft.issn=1435-1803&rft.eissn=1435-1803&rft_id=info:doi/10.1007/s00395-024-01057-x&rft_dat=%3Cproquest_pubme%3E3062527635%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3114276031&rft_id=info:pmid/38811421&rfr_iscdi=true |