Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice
Background Sphingosine-1-phosphate receptor 2 (S1P2 ) is expressed in vascular endothelial cells (ECs). However, the role of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, comprom...
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| Veröffentlicht in: | Journal of allergy and clinical immunology 2013-11, Vol.132 (5), p.1205-1214.e9 |
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| creator | Cui, Hong, MD, PhD Okamoto, Yasuo, MD, PhD Yoshioka, Kazuaki, PhD Du, Wa, MD, PhD Takuwa, Noriko, MD, PhD Zhang, Wei, MD, PhD Asano, Masahide, PhD Shibamoto, Toshishige, MD, PhD Takuwa, Yoh, MD, PhD |
| description | Background Sphingosine-1-phosphate receptor 2 (S1P2 ) is expressed in vascular endothelial cells (ECs). However, the role of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2 -null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr -null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2 -null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2 -null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2 -deficient ECs showed more severe disassembly of adherens junctions with augmented S -nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. |
| doi_str_mv | 10.1016/j.jaci.2013.07.026 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1448223102</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>1_s2_0_S0091674913011512</els_id><sourcerecordid>3239595061</sourcerecordid><originalsourceid>FETCH-LOGICAL-c652t-ebb370324b784d15abe4157b26c56f926f29928c26daa31e9d3e0f9ce45414013</originalsourceid><addsrcrecordid>eNp9ktuKFDEQhhtR3HH1BbyQgAje9JhTHwIiyOIJFrxYvQ7pdPV0ZnuSNpUW5wl8bdPM6MJeeBUKvr9Sf_1VFM8Z3TLK6jf77d5Yt-WUiS1ttpTXD4oNo6op65ZXD4sNpYqVdSPVRfEEcU9zLVr1uLjgknJWNXxT_L6ZR-d3AZ2HkpXzGHAeTQISwcKcQiSczDEksAmJ2RnnMRHjzTweJ2OTswTHYG9JGmNYdiPBZZ4jILrgSRgI-D6kESZnJuJdipkPv1wPBI8-jQaBOE8OzsLT4tFgJoRn5_ey-P7xw7erz-X1109frt5fl7aueCqh60RDBZdd08qeVaYDmY10vLZVPSheD1wp3lpe98YIBqoXQAdlQVaSybyoy-L1qW829WMBTPrg0MI0GQ9hQc2kbDkXjPKMvryH7sMSfZ5Os4rKVjLB14b8RNkYECMMeo7uYOJRM6rXmPRerzHpNSZNG51jyqIX59ZLd4D-n-RvLhl4dQYMWjMN0Xjr8I5rlBBMqcy9PXGQd_bTQdRoHXgLvcsBJt0H9_853t2T28l5l3-8hSPgnV-NXFN9sx7Uek9MUMYqxsUfvnzGtQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1504841321</pqid></control><display><type>article</type><title>Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Cui, Hong, MD, PhD ; Okamoto, Yasuo, MD, PhD ; Yoshioka, Kazuaki, PhD ; Du, Wa, MD, PhD ; Takuwa, Noriko, MD, PhD ; Zhang, Wei, MD, PhD ; Asano, Masahide, PhD ; Shibamoto, Toshishige, MD, PhD ; Takuwa, Yoh, MD, PhD</creator><creatorcontrib>Cui, Hong, MD, PhD ; Okamoto, Yasuo, MD, PhD ; Yoshioka, Kazuaki, PhD ; Du, Wa, MD, PhD ; Takuwa, Noriko, MD, PhD ; Zhang, Wei, MD, PhD ; Asano, Masahide, PhD ; Shibamoto, Toshishige, MD, PhD ; Takuwa, Yoh, MD, PhD</creatorcontrib><description>Background Sphingosine-1-phosphate receptor 2 (S1P2 ) is expressed in vascular endothelial cells (ECs). However, the role of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2 -null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr -null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2 -null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2 -null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2 -deficient ECs showed more severe disassembly of adherens junctions with augmented S -nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2013.07.026</identifier><identifier>PMID: 24021572</identifier><identifier>CODEN: JACIBY</identifier><language>eng</language><publisher>New York, NY: Mosby, Inc</publisher><subject>adherens junction ; Adherens Junctions - metabolism ; Allergy and Immunology ; anaphylaxis ; Anaphylaxis - genetics ; Anaphylaxis - metabolism ; Anaphylaxis - mortality ; Animals ; Aorta - immunology ; Aorta - metabolism ; beta Catenin - metabolism ; Biological and medical sciences ; Capillary Permeability - genetics ; Capillary Permeability - immunology ; Disease Models, Animal ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; endothelial nitric oxide synthase ; Enzyme Activation ; Experiments ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Gene Deletion ; Heart rate ; Immunopathology ; Kinases ; Lung - immunology ; Lung - metabolism ; Medical sciences ; Mice ; Mice, Knockout ; NG-Nitroarginine Methyl Ester - pharmacology ; Nitric oxide ; Nitric Oxide Synthase Type III - antagonists & inhibitors ; Nitric Oxide Synthase Type III - genetics ; Nitric Oxide Synthase Type III - metabolism ; nitrosylation ; Permeability ; Phosphorylation ; Plasma ; Platelet Activating Factor - pharmacology ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Receptors, Lysosphingolipid - genetics ; Receptors, Lysosphingolipid - metabolism ; Rodents ; S1P2 ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Signal Transduction ; Software ; Sphingosine-1-phosphate ; vascular permeability ; VE-cadherin ; β-catenin</subject><ispartof>Journal of allergy and clinical immunology, 2013-11, Vol.132 (5), p.1205-1214.e9</ispartof><rights>American Academy of Allergy, Asthma & Immunology</rights><rights>2013 American Academy of Allergy, Asthma & Immunology</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Nov 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c652t-ebb370324b784d15abe4157b26c56f926f29928c26daa31e9d3e0f9ce45414013</citedby><cites>FETCH-LOGICAL-c652t-ebb370324b784d15abe4157b26c56f926f29928c26daa31e9d3e0f9ce45414013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674913011512$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27933199$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24021572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Hong, MD, PhD</creatorcontrib><creatorcontrib>Okamoto, Yasuo, MD, PhD</creatorcontrib><creatorcontrib>Yoshioka, Kazuaki, PhD</creatorcontrib><creatorcontrib>Du, Wa, MD, PhD</creatorcontrib><creatorcontrib>Takuwa, Noriko, MD, PhD</creatorcontrib><creatorcontrib>Zhang, Wei, MD, PhD</creatorcontrib><creatorcontrib>Asano, Masahide, PhD</creatorcontrib><creatorcontrib>Shibamoto, Toshishige, MD, PhD</creatorcontrib><creatorcontrib>Takuwa, Yoh, MD, PhD</creatorcontrib><title>Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Background Sphingosine-1-phosphate receptor 2 (S1P2 ) is expressed in vascular endothelial cells (ECs). However, the role of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2 -null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr -null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2 -null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2 -null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2 -deficient ECs showed more severe disassembly of adherens junctions with augmented S -nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis.</description><subject>adherens junction</subject><subject>Adherens Junctions - metabolism</subject><subject>Allergy and Immunology</subject><subject>anaphylaxis</subject><subject>Anaphylaxis - genetics</subject><subject>Anaphylaxis - metabolism</subject><subject>Anaphylaxis - mortality</subject><subject>Animals</subject><subject>Aorta - immunology</subject><subject>Aorta - metabolism</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Capillary Permeability - genetics</subject><subject>Capillary Permeability - immunology</subject><subject>Disease Models, Animal</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>endothelial nitric oxide synthase</subject><subject>Enzyme Activation</subject><subject>Experiments</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Gene Deletion</subject><subject>Heart rate</subject><subject>Immunopathology</subject><subject>Kinases</subject><subject>Lung - immunology</subject><subject>Lung - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>NG-Nitroarginine Methyl Ester - pharmacology</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type III - antagonists & inhibitors</subject><subject>Nitric Oxide Synthase Type III - genetics</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>nitrosylation</subject><subject>Permeability</subject><subject>Phosphorylation</subject><subject>Plasma</subject><subject>Platelet Activating Factor - pharmacology</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptors, Lysosphingolipid - genetics</subject><subject>Receptors, Lysosphingolipid - metabolism</subject><subject>Rodents</subject><subject>S1P2</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Signal Transduction</subject><subject>Software</subject><subject>Sphingosine-1-phosphate</subject><subject>vascular permeability</subject><subject>VE-cadherin</subject><subject>β-catenin</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ktuKFDEQhhtR3HH1BbyQgAje9JhTHwIiyOIJFrxYvQ7pdPV0ZnuSNpUW5wl8bdPM6MJeeBUKvr9Sf_1VFM8Z3TLK6jf77d5Yt-WUiS1ttpTXD4oNo6op65ZXD4sNpYqVdSPVRfEEcU9zLVr1uLjgknJWNXxT_L6ZR-d3AZ2HkpXzGHAeTQISwcKcQiSczDEksAmJ2RnnMRHjzTweJ2OTswTHYG9JGmNYdiPBZZ4jILrgSRgI-D6kESZnJuJdipkPv1wPBI8-jQaBOE8OzsLT4tFgJoRn5_ey-P7xw7erz-X1109frt5fl7aueCqh60RDBZdd08qeVaYDmY10vLZVPSheD1wp3lpe98YIBqoXQAdlQVaSybyoy-L1qW829WMBTPrg0MI0GQ9hQc2kbDkXjPKMvryH7sMSfZ5Os4rKVjLB14b8RNkYECMMeo7uYOJRM6rXmPRerzHpNSZNG51jyqIX59ZLd4D-n-RvLhl4dQYMWjMN0Xjr8I5rlBBMqcy9PXGQd_bTQdRoHXgLvcsBJt0H9_853t2T28l5l3-8hSPgnV-NXFN9sx7Uek9MUMYqxsUfvnzGtQ</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Cui, Hong, MD, PhD</creator><creator>Okamoto, Yasuo, MD, PhD</creator><creator>Yoshioka, Kazuaki, PhD</creator><creator>Du, Wa, MD, PhD</creator><creator>Takuwa, Noriko, MD, PhD</creator><creator>Zhang, Wei, MD, PhD</creator><creator>Asano, Masahide, PhD</creator><creator>Shibamoto, Toshishige, MD, PhD</creator><creator>Takuwa, Yoh, MD, PhD</creator><general>Mosby, Inc</general><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</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>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20131101</creationdate><title>Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice</title><author>Cui, Hong, MD, PhD ; Okamoto, Yasuo, MD, PhD ; Yoshioka, Kazuaki, PhD ; Du, Wa, MD, PhD ; Takuwa, Noriko, MD, PhD ; Zhang, Wei, MD, PhD ; Asano, Masahide, PhD ; Shibamoto, Toshishige, MD, PhD ; Takuwa, Yoh, MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c652t-ebb370324b784d15abe4157b26c56f926f29928c26daa31e9d3e0f9ce45414013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>adherens junction</topic><topic>Adherens Junctions - metabolism</topic><topic>Allergy and Immunology</topic><topic>anaphylaxis</topic><topic>Anaphylaxis - genetics</topic><topic>Anaphylaxis - metabolism</topic><topic>Anaphylaxis - mortality</topic><topic>Animals</topic><topic>Aorta - immunology</topic><topic>Aorta - metabolism</topic><topic>beta Catenin - metabolism</topic><topic>Biological and medical sciences</topic><topic>Capillary Permeability - genetics</topic><topic>Capillary Permeability - immunology</topic><topic>Disease Models, Animal</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>endothelial nitric oxide synthase</topic><topic>Enzyme Activation</topic><topic>Experiments</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Gene Deletion</topic><topic>Heart rate</topic><topic>Immunopathology</topic><topic>Kinases</topic><topic>Lung - immunology</topic><topic>Lung - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>NG-Nitroarginine Methyl Ester - pharmacology</topic><topic>Nitric oxide</topic><topic>Nitric Oxide Synthase Type III - antagonists & inhibitors</topic><topic>Nitric Oxide Synthase Type III - genetics</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>nitrosylation</topic><topic>Permeability</topic><topic>Phosphorylation</topic><topic>Plasma</topic><topic>Platelet Activating Factor - pharmacology</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptors, Lysosphingolipid - genetics</topic><topic>Receptors, Lysosphingolipid - metabolism</topic><topic>Rodents</topic><topic>S1P2</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Signal Transduction</topic><topic>Software</topic><topic>Sphingosine-1-phosphate</topic><topic>vascular permeability</topic><topic>VE-cadherin</topic><topic>β-catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Hong, MD, PhD</creatorcontrib><creatorcontrib>Okamoto, Yasuo, MD, PhD</creatorcontrib><creatorcontrib>Yoshioka, Kazuaki, PhD</creatorcontrib><creatorcontrib>Du, Wa, MD, PhD</creatorcontrib><creatorcontrib>Takuwa, Noriko, MD, PhD</creatorcontrib><creatorcontrib>Zhang, Wei, MD, PhD</creatorcontrib><creatorcontrib>Asano, Masahide, PhD</creatorcontrib><creatorcontrib>Shibamoto, Toshishige, MD, PhD</creatorcontrib><creatorcontrib>Takuwa, Yoh, MD, PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Hong, MD, PhD</au><au>Okamoto, Yasuo, MD, PhD</au><au>Yoshioka, Kazuaki, PhD</au><au>Du, Wa, MD, PhD</au><au>Takuwa, Noriko, MD, PhD</au><au>Zhang, Wei, MD, PhD</au><au>Asano, Masahide, PhD</au><au>Shibamoto, Toshishige, MD, PhD</au><au>Takuwa, Yoh, MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>132</volume><issue>5</issue><spage>1205</spage><epage>1214.e9</epage><pages>1205-1214.e9</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><coden>JACIBY</coden><abstract>Background Sphingosine-1-phosphate receptor 2 (S1P2 ) is expressed in vascular endothelial cells (ECs). However, the role of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2 -null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr -null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2 -null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2 -null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2 -deficient ECs showed more severe disassembly of adherens junctions with augmented S -nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis.</abstract><cop>New York, NY</cop><pub>Mosby, Inc</pub><pmid>24021572</pmid><doi>10.1016/j.jaci.2013.07.026</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0091-6749 1097-6825 |
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| source | MEDLINE; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | adherens junction Adherens Junctions - metabolism Allergy and Immunology anaphylaxis Anaphylaxis - genetics Anaphylaxis - metabolism Anaphylaxis - mortality Animals Aorta - immunology Aorta - metabolism beta Catenin - metabolism Biological and medical sciences Capillary Permeability - genetics Capillary Permeability - immunology Disease Models, Animal Endothelial Cells - drug effects Endothelial Cells - metabolism endothelial nitric oxide synthase Enzyme Activation Experiments Fundamental and applied biological sciences. Psychology Fundamental immunology Gene Deletion Heart rate Immunopathology Kinases Lung - immunology Lung - metabolism Medical sciences Mice Mice, Knockout NG-Nitroarginine Methyl Ester - pharmacology Nitric oxide Nitric Oxide Synthase Type III - antagonists & inhibitors Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - metabolism nitrosylation Permeability Phosphorylation Plasma Platelet Activating Factor - pharmacology Proteins Proto-Oncogene Proteins c-akt - metabolism Receptors, Lysosphingolipid - genetics Receptors, Lysosphingolipid - metabolism Rodents S1P2 Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Signal Transduction Software Sphingosine-1-phosphate vascular permeability VE-cadherin β-catenin |
| title | Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T00%3A41%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Sphingosine-1-phosphate%20receptor%202%20protects%20against%20anaphylactic%20shock%20through%20suppression%20of%20endothelial%20nitric%20oxide%20synthase%20in%20mice&rft.jtitle=Journal%20of%20allergy%20and%20clinical%20immunology&rft.au=Cui,%20Hong,%20MD,%20PhD&rft.date=2013-11-01&rft.volume=132&rft.issue=5&rft.spage=1205&rft.epage=1214.e9&rft.pages=1205-1214.e9&rft.issn=0091-6749&rft.eissn=1097-6825&rft.coden=JACIBY&rft_id=info:doi/10.1016/j.jaci.2013.07.026&rft_dat=%3Cproquest_cross%3E3239595061%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1504841321&rft_id=info:pmid/24021572&rft_els_id=1_s2_0_S0091674913011512&rfr_iscdi=true |