Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand
We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the protease activated receptor 1 (PAR-1)-dependent signaling specificity of thrombin from a disruptive to a protective effect in cultured human umb...
Gespeichert in:
| Veröffentlicht in: | Thrombosis and haemostasis Jg. 100; H. 1; S. 101 |
|---|---|
| Hauptverfasser: | , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
Germany
01.07.2008
|
| Schlagworte: | |
| ISSN: | 0340-6245 |
| Online-Zugang: | Weitere Angaben |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Abstract | We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the protease activated receptor 1 (PAR-1)-dependent signaling specificity of thrombin from a disruptive to a protective effect in cultured human umbilical vein endothelial cells. Given the phenotypic differences between endothelial cells in venular and arterial beds, in this study we evaluated the signaling function of thrombin in human pulmonary artery endothelial cells (HPAECs) before and after treating them with PC-S195A which lacks catalytic activity but exhibits a normal affinity for EPCR. As expected, both thrombin and thrombin receptor agonist peptide (TRAP) enhanced the permeability barrier of HPAECs; however, both PAR-1 agonists exhibited a potent barrier protective effect when the cells were treated with PC-S195A prior to stimulation by the agonists. Interestingly, similar to APC, thrombin exhibited a potent cytoprotective activity in the LPS-induced permeability and TNF-alpha-induced apoptosis and adhesion assays in the PC-S195A treated HPAECs. Treatment of HPAECs with the cholesterol depleting molecule methyl-beta-cyclodextrin eliminated the protective effect of both APC and thrombin. These results suggest that the occupancy of EPCR by its natural ligand recruits PAR-1 to a protective signaling pathway within lipid rafts of HPAECs. Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR. These findings may have important ramifications for understanding the mechanism of the participation of the vascular PAR-1 in pathophysiology of the inflammatory disorders. |
|---|---|
| AbstractList | We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the protease activated receptor 1 (PAR-1)-dependent signaling specificity of thrombin from a disruptive to a protective effect in cultured human umbilical vein endothelial cells. Given the phenotypic differences between endothelial cells in venular and arterial beds, in this study we evaluated the signaling function of thrombin in human pulmonary artery endothelial cells (HPAECs) before and after treating them with PC-S195A which lacks catalytic activity but exhibits a normal affinity for EPCR. As expected, both thrombin and thrombin receptor agonist peptide (TRAP) enhanced the permeability barrier of HPAECs; however, both PAR-1 agonists exhibited a potent barrier protective effect when the cells were treated with PC-S195A prior to stimulation by the agonists. Interestingly, similar to APC, thrombin exhibited a potent cytoprotective activity in the LPS-induced permeability and TNF-alpha-induced apoptosis and adhesion assays in the PC-S195A treated HPAECs. Treatment of HPAECs with the cholesterol depleting molecule methyl-beta-cyclodextrin eliminated the protective effect of both APC and thrombin. These results suggest that the occupancy of EPCR by its natural ligand recruits PAR-1 to a protective signaling pathway within lipid rafts of HPAECs. Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR. These findings may have important ramifications for understanding the mechanism of the participation of the vascular PAR-1 in pathophysiology of the inflammatory disorders. We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the protease activated receptor 1 (PAR-1)-dependent signaling specificity of thrombin from a disruptive to a protective effect in cultured human umbilical vein endothelial cells. Given the phenotypic differences between endothelial cells in venular and arterial beds, in this study we evaluated the signaling function of thrombin in human pulmonary artery endothelial cells (HPAECs) before and after treating them with PC-S195A which lacks catalytic activity but exhibits a normal affinity for EPCR. As expected, both thrombin and thrombin receptor agonist peptide (TRAP) enhanced the permeability barrier of HPAECs; however, both PAR-1 agonists exhibited a potent barrier protective effect when the cells were treated with PC-S195A prior to stimulation by the agonists. Interestingly, similar to APC, thrombin exhibited a potent cytoprotective activity in the LPS-induced permeability and TNF-alpha-induced apoptosis and adhesion assays in the PC-S195A treated HPAECs. Treatment of HPAECs with the cholesterol depleting molecule methyl-beta-cyclodextrin eliminated the protective effect of both APC and thrombin. These results suggest that the occupancy of EPCR by its natural ligand recruits PAR-1 to a protective signaling pathway within lipid rafts of HPAECs. Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR. These findings may have important ramifications for understanding the mechanism of the participation of the vascular PAR-1 in pathophysiology of the inflammatory disorders.We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the protease activated receptor 1 (PAR-1)-dependent signaling specificity of thrombin from a disruptive to a protective effect in cultured human umbilical vein endothelial cells. Given the phenotypic differences between endothelial cells in venular and arterial beds, in this study we evaluated the signaling function of thrombin in human pulmonary artery endothelial cells (HPAECs) before and after treating them with PC-S195A which lacks catalytic activity but exhibits a normal affinity for EPCR. As expected, both thrombin and thrombin receptor agonist peptide (TRAP) enhanced the permeability barrier of HPAECs; however, both PAR-1 agonists exhibited a potent barrier protective effect when the cells were treated with PC-S195A prior to stimulation by the agonists. Interestingly, similar to APC, thrombin exhibited a potent cytoprotective activity in the LPS-induced permeability and TNF-alpha-induced apoptosis and adhesion assays in the PC-S195A treated HPAECs. Treatment of HPAECs with the cholesterol depleting molecule methyl-beta-cyclodextrin eliminated the protective effect of both APC and thrombin. These results suggest that the occupancy of EPCR by its natural ligand recruits PAR-1 to a protective signaling pathway within lipid rafts of HPAECs. Based on these results we conclude that the activation of PAR-1 by thrombin would initiate a protective response in intact arterial vascular cells expressing EPCR. These findings may have important ramifications for understanding the mechanism of the participation of the vascular PAR-1 in pathophysiology of the inflammatory disorders. |
| Author | Bae, Jong-Sup Rezaie, Alireza R |
| Author_xml | – sequence: 1 givenname: Jong-Sup surname: Bae fullname: Bae, Jong-Sup organization: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA – sequence: 2 givenname: Alireza R surname: Rezaie fullname: Rezaie, Alireza R |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/18612544$$D View this record in MEDLINE/PubMed |
| BookMark | eNpVUEFOwzAQ9KGIlsKNM_IJwSGwdhwnOVYVUKRKVKj3yEm21CixQ-wg9Wu8DhdaIU4j7c7OzM4ZGRlrkJBLBneMSbhfLyCLgEfAeDoiE4gFRJKLZEzOnHsHYFLkySkZs0wynggxIV-r3npUDqmqvP5UHmvaY4Wdtz1l9GY1e43Y7XGpraHljvptb9tSG6od7fb3-y3SMNgOrTK0G5rWGtXvqOo9BkBTW7_FRquGVtg0jurNv-GPSrif_5kHbVtVQ6dDouCpvaNG-aEP7Ea_KVOfk5ONahxeHHBK1o8P6_kiWr48Pc9ny6iScZ5GOYshiaVUgvMSylRkNSR5xTYZL1MV-hCK8TqtkNciwTyDXMRJzTPgkJaZ5FNy_SsbMn4M6HzRard_Qhm0gytkHgOkqQjEqwNxKFusi67XbeigOJbNvwGZGYKI |
| CitedBy_id | crossref_primary_10_1073_pnas_2022248118 crossref_primary_10_1038_s41392_021_00816_9 crossref_primary_10_1002_advs_202201883 crossref_primary_10_1074_jbc_M110_163642 crossref_primary_10_1182_blood_2014_09_599910 crossref_primary_10_1038_icb_2008_107 crossref_primary_10_1016_j_thromres_2012_03_003 crossref_primary_10_1007_s10753_011_9394_5 crossref_primary_10_1160_TH14_03_0233 crossref_primary_10_1002_jcp_21718 crossref_primary_10_5483_BMBRep_2012_45_3_200 crossref_primary_10_3390_ijms21145086 crossref_primary_10_1111_jcmm_12891 crossref_primary_10_1002_iub_447 crossref_primary_10_1371_journal_pone_0101446 crossref_primary_10_1111_apha_12264 crossref_primary_10_1160_th14_05_0448 crossref_primary_10_1016_j_brainres_2015_04_002 crossref_primary_10_5483_BMBRep_2012_45_7_065 crossref_primary_10_1002_j_2040_4603_2013_tb00479_x crossref_primary_10_1007_s00380_018_01324_7 crossref_primary_10_1182_blood_2013_03_488957 crossref_primary_10_1038_s41598_022_15592_x crossref_primary_10_1097_MOH_0000000000000364 crossref_primary_10_1002_jcp_22249 crossref_primary_10_1160_th14_02_0167 crossref_primary_10_1016_j_fct_2012_06_013 crossref_primary_10_1016_j_lfs_2021_120045 crossref_primary_10_1016_j_fct_2012_11_040 crossref_primary_10_1007_s00281_011_0281_9 crossref_primary_10_1002_jcb_24361 crossref_primary_10_1016_j_taap_2012_04_025 crossref_primary_10_1007_s00011_011_0330_9 crossref_primary_10_1007_s12272_013_0233_0 crossref_primary_10_5483_BMBRep_2013_46_10_028 crossref_primary_10_1016_j_taap_2013_01_008 crossref_primary_10_1016_j_transproceed_2016_02_080 crossref_primary_10_1016_j_taap_2014_09_003 crossref_primary_10_1007_s10753_014_9883_4 crossref_primary_10_1016_j_vph_2013_01_005 crossref_primary_10_1155_2012_614545 crossref_primary_10_1007_s00011_013_0689_x crossref_primary_10_1002_rth2_12011 crossref_primary_10_5483_BMBRep_2013_46_11_056 crossref_primary_10_1002_jcb_23172 crossref_primary_10_1002_jcp_24243 crossref_primary_10_1002_jcp_24485 crossref_primary_10_1016_j_fct_2013_04_027 crossref_primary_10_1182_blood_2009_05_219485 crossref_primary_10_1182_blood_2014_06_582775 crossref_primary_10_1016_j_mvr_2008_09_002 crossref_primary_10_1093_neuopn_okaa014 crossref_primary_10_1016_j_fitote_2013_08_004 crossref_primary_10_1007_s12272_014_0403_8 crossref_primary_10_1007_s10753_014_9919_9 crossref_primary_10_1111_j_1538_7836_2012_04832_x crossref_primary_10_1007_s10753_011_9414_5 crossref_primary_10_3390_ijms21218065 crossref_primary_10_1038_s41598_018_33222_3 crossref_primary_10_1111_j_1365_2796_2011_02354_x crossref_primary_10_3390_ijms232113130 crossref_primary_10_1002_jcp_24214 crossref_primary_10_1016_j_fct_2012_02_026 crossref_primary_10_1134_S0006297917070033 crossref_primary_10_1007_s10753_012_9523_9 crossref_primary_10_5012_bkcs_2014_35_10_2955 crossref_primary_10_1007_s00011_014_0708_6 crossref_primary_10_1089_jmf_2022_K_0099 crossref_primary_10_1007_s12272_014_0501_7 crossref_primary_10_1124_mol_116_106526 crossref_primary_10_3390_ijms18061144 crossref_primary_10_1111_j_1538_7836_2009_03337_x crossref_primary_10_1007_s00011_011_0381_y crossref_primary_10_5482_ha_1162 crossref_primary_10_1002_jbm_a_34007 crossref_primary_10_1016_j_fct_2011_12_004 crossref_primary_10_1182_blood_2011_06_360701 crossref_primary_10_1182_blood_2010_10_314773 crossref_primary_10_1016_j_fitote_2013_11_006 crossref_primary_10_1002_jcb_24163 crossref_primary_10_1007_s12185_012_1059_0 crossref_primary_10_1111_j_1600_6143_2012_04122_x crossref_primary_10_1182_blood_2009_03_209981 crossref_primary_10_1002_adma_201503093 crossref_primary_10_3390_molecules21050676 crossref_primary_10_1007_s00011_011_0403_9 crossref_primary_10_1016_j_fct_2010_03_045 crossref_primary_10_1002_lt_25929 crossref_primary_10_1016_j_fct_2012_03_082 crossref_primary_10_5483_BMBRep_2012_45_4_221 crossref_primary_10_1016_j_intimp_2025_114218 crossref_primary_10_1111_j_1538_7836_2010_03812_x crossref_primary_10_1007_s00011_011_0430_6 crossref_primary_10_1182_blood_2016_06_720581 crossref_primary_10_5483_BMBRep_2014_47_7_195 crossref_primary_10_1002_jcp_24568 crossref_primary_10_1517_17460440902721204 crossref_primary_10_1111_jth_15221 crossref_primary_10_1142_S0192415X13500882 crossref_primary_10_1016_j_thromres_2009_07_015 crossref_primary_10_1160_TH11_11_0766 crossref_primary_10_1016_j_fitote_2014_07_006 crossref_primary_10_1016_j_jff_2015_04_053 |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1160/TH08-02-0127 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine |
| ExternalDocumentID | 18612544 |
| Genre | Journal Article Research Support, N.I.H., Extramural |
| GrantInformation_xml | – fundername: NHLBI NIH HHS grantid: HL 68571 – fundername: NHLBI NIH HHS grantid: R01 HL068571 – fundername: NHLBI NIH HHS grantid: R01 HL062565 – fundername: NHLBI NIH HHS grantid: HL 62565 |
| GroupedDBID | --- .55 .GJ 0R~ 0VX 123 1KJ 4.4 53G 5RE AAQQT ABJNI ABOCM ACGFO ACGFS ACNUY AENEX AFFNX AGCGI AHRSK ALMA_UNASSIGNED_HOLDINGS BR6 C45 CGR CS3 CUY CVF DU5 EBS ECM EIF EJD F5P H13 J5H NPM OVD P2P RTC RTE SJN TEORI X7M ZGI ZXP 7X8 |
| ID | FETCH-LOGICAL-c6397-91305366a422b0b748d059c1f82b7a4954a12d7ce2d45e9809435d280207b862 |
| IEDL.DBID | 7X8 |
| ISSN | 0340-6245 |
| IngestDate | Thu Jul 10 23:26:34 EDT 2025 Mon Jul 21 05:36:33 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 1 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c6397-91305366a422b0b748d059c1f82b7a4954a12d7ce2d45e9809435d280207b862 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | http://www.thieme-connect.de/products/ejournals/pdf/10.1160/TH08-02-0127.pdf |
| PMID | 18612544 |
| PQID | 69300774 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_69300774 pubmed_primary_18612544 |
| PublicationCentury | 2000 |
| PublicationDate | 2008-07-00 |
| PublicationDateYYYYMMDD | 2008-07-01 |
| PublicationDate_xml | – month: 07 year: 2008 text: 2008-07-00 |
| PublicationDecade | 2000 |
| PublicationPlace | Germany |
| PublicationPlace_xml | – name: Germany |
| PublicationTitle | Thrombosis and haemostasis |
| PublicationTitleAlternate | Thromb Haemost |
| PublicationYear | 2008 |
| SSID | ssj0016495 |
| Score | 2.2892103 |
| Snippet | We recently demonstrated that the occupancy of endothelial protein C receptor (EPCR) by its natural ligand activated protein C (APC)/protein C switches the... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 101 |
| SubjectTerms | Antigens, CD - metabolism Apoptosis beta-Cyclodextrins - pharmacology Capillary Permeability Caveolin 1 - metabolism Cell Adhesion Cell Line, Tumor Cells, Cultured Cholesterol - deficiency Cytoprotection Dose-Response Relationship, Drug Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelial Cells - pathology Endothelial Protein C Receptor Humans Inflammation - metabolism Ligands Lipopolysaccharides - pharmacology Membrane Microdomains - metabolism Monocytes - metabolism Mutation Peptides - pharmacology Protein C - genetics Protein C - metabolism Pulmonary Artery - drug effects Pulmonary Artery - metabolism Pulmonary Artery - pathology Receptor, PAR-1 - agonists Receptor, PAR-1 - genetics Receptor, PAR-1 - metabolism Receptors, Cell Surface - metabolism Receptors, Lysosphingolipid - metabolism Receptors, Thrombin - metabolism RNA Interference RNA, Small Interfering - metabolism Signal Transduction - drug effects Thrombin - metabolism Tumor Necrosis Factor-alpha - metabolism |
| Title | Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/18612544 https://www.proquest.com/docview/69300774 |
| Volume | 100 |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV09b9swECXSpiiyNEmbNm6-bsjQDkIkihJpoEAQGAkyxIYRePBmkCJZCHBl17IN-K_11_WOlmB0KDJk0UCJpIQ7Ht_pHu8Yu9aKF9p1RZQlzqODYnXU1bqIYh8XMvep1y5I-kkOBmo87g732I_2LAzRKlubGAy1nRX0j_yGSvbFiFVu578jqhlFsdWmgMYbtp8ikCGdluNdDCEXoeZKnBLBnYuspb3n8c3okYL-xEng8v_QMmwxD4eve7kj9qGBlnC31YVjtueqj-x9vwmef2J_hpSTAXctoMMMawSZFtDeuTm63ZDAt-Hdc5R8b2-ivMBsgMoo_ELvGcoampwOaB8BG0J1P5ivpji9XmwgkEM34CpLh7qmqNdAUYEaSv9PYxgF-_d2k-PYM8p2jHCY5iyXNYSEo_j0tPypK3vCRg_3o95j1JRuiAqKFFI8H1d3nmvBuYmNFMoijisSr7iRGgUjdMKtLBy3InNdRfzGzHKF4FUadLI-s7fVrHKnDJTPc29Sa5JUCKNTZTIhdYYtkscmFh121YpkgiuDPkxXbraqJ61QOuzLVqqT-TaBxyRRhOuE-Ppi3zN2sCWIED_3nO17tAnugr0r1suyXlwGhcPrYNj_C2Wx4yU |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Protease+activated+receptor+1+%28PAR-1%29+activation+by+thrombin+is+protective+in+human+pulmonary+artery+endothelial+cells+if+endothelial+protein+C+receptor+is+occupied+by+its+natural+ligand&rft.jtitle=Thrombosis+and+haemostasis&rft.au=Bae%2C+Jong-Sup&rft.au=Rezaie%2C+Alireza+R&rft.date=2008-07-01&rft.issn=0340-6245&rft.volume=100&rft.issue=1&rft.spage=101&rft_id=info:doi/10.1160%2FTH08-02-0127&rft_id=info%3Apmid%2F18612544&rft_id=info%3Apmid%2F18612544&rft.externalDocID=18612544 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0340-6245&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0340-6245&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0340-6245&client=summon |