Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads
Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the th...
Uložené v:
| Vydané v: | The Journal of biological chemistry Ročník 277; číslo 51; s. 49815 |
|---|---|
| Hlavní autori: | , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
20.12.2002
|
| Predmet: | |
| ISSN: | 0021-9258 |
| On-line prístup: | Zistit podrobnosti o prístupe |
| Tagy: |
Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
|
| Abstract | Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent generation of activated protein C. We have found that tumor necrosis factor-beta (TGF-beta)-dependent suppression of TM on endothelial cells is differentially regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in activation of a TGF-beta reporter alone and enhanced TGF-beta response. Moreover, Smad6s overexpression suppressed TM and subsequently reduced activated protein C generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent activation of protein C, whereas blocking the inhibitory Smad7 by antisense resulted in reduced TM-dependent activation of protein C. The effect of Smad6s appeared to be due, at least in part, to up-regulation of TGF-beta itself. Immunohistochemistry studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque. Consistent with the in vitro data, we found differential expression of Smad6s and Smad7 in normal versus atherosclerotic vessels, with Smad6s expression low in normal vessels but elevated in atherosclerotic vessels. In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation. |
|---|---|
| AbstractList | Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent generation of activated protein C. We have found that tumor necrosis factor-beta (TGF-beta)-dependent suppression of TM on endothelial cells is differentially regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in activation of a TGF-beta reporter alone and enhanced TGF-beta response. Moreover, Smad6s overexpression suppressed TM and subsequently reduced activated protein C generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent activation of protein C, whereas blocking the inhibitory Smad7 by antisense resulted in reduced TM-dependent activation of protein C. The effect of Smad6s appeared to be due, at least in part, to up-regulation of TGF-beta itself. Immunohistochemistry studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque. Consistent with the in vitro data, we found differential expression of Smad6s and Smad7 in normal versus atherosclerotic vessels, with Smad6s expression low in normal vessels but elevated in atherosclerotic vessels. In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation.Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent generation of activated protein C. We have found that tumor necrosis factor-beta (TGF-beta)-dependent suppression of TM on endothelial cells is differentially regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in activation of a TGF-beta reporter alone and enhanced TGF-beta response. Moreover, Smad6s overexpression suppressed TM and subsequently reduced activated protein C generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent activation of protein C, whereas blocking the inhibitory Smad7 by antisense resulted in reduced TM-dependent activation of protein C. The effect of Smad6s appeared to be due, at least in part, to up-regulation of TGF-beta itself. Immunohistochemistry studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque. Consistent with the in vitro data, we found differential expression of Smad6s and Smad7 in normal versus atherosclerotic vessels, with Smad6s expression low in normal vessels but elevated in atherosclerotic vessels. In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation. Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent generation of activated protein C. We have found that tumor necrosis factor-beta (TGF-beta)-dependent suppression of TM on endothelial cells is differentially regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in activation of a TGF-beta reporter alone and enhanced TGF-beta response. Moreover, Smad6s overexpression suppressed TM and subsequently reduced activated protein C generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent activation of protein C, whereas blocking the inhibitory Smad7 by antisense resulted in reduced TM-dependent activation of protein C. The effect of Smad6s appeared to be due, at least in part, to up-regulation of TGF-beta itself. Immunohistochemistry studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque. Consistent with the in vitro data, we found differential expression of Smad6s and Smad7 in normal versus atherosclerotic vessels, with Smad6s expression low in normal vessels but elevated in atherosclerotic vessels. In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation. |
| Author | Myers, Laura Grinnell, Brian W Sandusky, George Berg, David T Richardson, Mark A |
| Author_xml | – sequence: 1 givenname: George surname: Sandusky fullname: Sandusky, George organization: Division of Research Technologies, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA – sequence: 2 givenname: David T surname: Berg fullname: Berg, David T – sequence: 3 givenname: Mark A surname: Richardson fullname: Richardson, Mark A – sequence: 4 givenname: Laura surname: Myers fullname: Myers, Laura – sequence: 5 givenname: Brian W surname: Grinnell fullname: Grinnell, Brian W |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/12407115$$D View this record in MEDLINE/PubMed |
| BookMark | eNo9kL1PwzAQxT0U0Q9YGVEmthTbseNkRBVfUhED3SMnPhNXiR1iB9H_HhcKN9xJ737v6XRLNLPOAkJXBK8JFux2XzfrhmLMWRb7DC0wpiQtKS_maOn9HsdiJTlHc0IZFoTwBTq8ODV1MhhnE6eT0I6ur11_FI1NFQxgFdiQyCaYz3-snXppk2F0AYxNNj-26b1NlNEaxsgb2SXwNYzg_ckSc1xooTtu3nqp_AU607LzcHmaK7R7uN9tntLt6-Pz5m6bNkzwkGomc2AZlFJhqkstaq0zXELO6qwuOZWKSJxLJaAoRC4I5gRKjTNOVQENpyt08xsbr_2YwIeqN76BrpMW3OQrQaOL5lkEr0_gVPegqmE0vRwP1d-v6DcHl27S |
| CitedBy_id | crossref_primary_10_1074_jbc_C400579200 crossref_primary_10_1124_jpet_107_119479 crossref_primary_10_1161_01_ATV_0000134298_25489_92 crossref_primary_10_1172_JCI31027 crossref_primary_10_1634_stemcells_2008_0800 crossref_primary_10_1097_01_CCM_0000128036_64448_9e crossref_primary_10_1097_BCR_0b013e3181b47eb8 crossref_primary_10_1016_j_diabet_2014_05_004 crossref_primary_10_1161_CIRCULATIONAHA_106_640698 crossref_primary_10_1007_s00281_011_0282_8 crossref_primary_10_1007_s11010_020_03872_x crossref_primary_10_1111_j_1464_5491_2012_03573_x crossref_primary_10_1177_154405910608500804 crossref_primary_10_1093_annonc_mdh131 crossref_primary_10_1161_01_RES_0000159707_05637_a1 crossref_primary_10_1016_j_jvs_2011_04_037 crossref_primary_10_1111_j_1464_5491_2007_02289_x crossref_primary_10_1016_j_thromres_2015_01_034 crossref_primary_10_1089_ten_tea_2009_0050 crossref_primary_10_1097_SAP_0b013e318180f2b2 crossref_primary_10_1155_2020_8864322 crossref_primary_10_1038_sj_onc_1207046 |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1074/jbc.c200543200 |
| 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 - Academic MEDLINE |
| 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 | Anatomy & Physiology Chemistry |
| ExternalDocumentID | 12407115 |
| Genre | Journal Article |
| GroupedDBID | --- -DZ -ET -~X .55 .GJ 0R~ 186 18M 2WC 34G 39C 3O- 53G 5BI 5GY 5RE 5VS 6TJ 79B 85S AAEDW AAFWJ AALRI AARDX AAXUO ABDNZ ABFSI ABOCM ABPPZ ABRJW ABTAH ACGFO ACNCT ADBBV ADIYS ADNWM ADVLN AENEX AEXQZ AFFNX AFOSN AFPKN AI. AITUG AKRWK ALMA_UNASSIGNED_HOLDINGS AMRAJ BTFSW C1A CGR CJ0 CS3 CUY CVF DIK DU5 E3Z EBS ECM EIF EJD F5P FA8 FDB FRP GROUPED_DOAJ GX1 H13 HH5 IH2 KQ8 L7B MVM N9A NHB NPM OHT OK1 P-O P0W P2P PKN R.V RHF RHI RNS ROL RPM SJN TBC TN5 TR2 UHB UKR UPT UQL VH1 VQA W8F WH7 WHG WOQ X7M XSW Y6R YQT YSK YWH YYP YZZ Z5M ZE2 ZGI ZY4 ~02 ~KM .7T 7X8 AAYWO ACVFH ADCNI ADXHL AEUPX AFPUW AIGII AKBMS AKYEP |
| ID | FETCH-LOGICAL-c475t-f4a6e43e9ad02f9f7bff309e64b3b952ad1a06ad7e887671051e9f0352d8ec52 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 29 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000180028900095&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0021-9258 |
| IngestDate | Fri Sep 05 12:42:49 EDT 2025 Wed Feb 19 02:29:53 EST 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 51 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c475t-f4a6e43e9ad02f9f7bff309e64b3b952ad1a06ad7e887671051e9f0352d8ec52 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | https://dx.doi.org/10.1074/jbc.C200543200 |
| PMID | 12407115 |
| PQID | 72767263 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_72767263 pubmed_primary_12407115 |
| PublicationCentury | 2000 |
| PublicationDate | 2002-12-20 |
| PublicationDateYYYYMMDD | 2002-12-20 |
| PublicationDate_xml | – month: 12 year: 2002 text: 2002-12-20 day: 20 |
| PublicationDecade | 2000 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | The Journal of biological chemistry |
| PublicationTitleAlternate | J Biol Chem |
| PublicationYear | 2002 |
| SSID | ssj0000491 |
| Score | 1.8498293 |
| Snippet | Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 49815 |
| SubjectTerms | Animals Arteriosclerosis - pathology Cell Survival Chloramphenicol O-Acetyltransferase - metabolism DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Down-Regulation Endothelium, Vascular - cytology Endothelium, Vascular - metabolism Enzyme-Linked Immunosorbent Assay Genes, Reporter Humans Immunohistochemistry Lymphotoxin-alpha - metabolism Oligonucleotides, Antisense - pharmacology Protein C - metabolism Signal Transduction Smad6 Protein Smad7 Protein Thrombomodulin - metabolism Time Factors Trans-Activators - metabolism Transcriptional Activation Transfection Transforming Growth Factor beta - metabolism Up-Regulation Xenopus Xenopus Proteins |
| Title | Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/12407115 https://www.proquest.com/docview/72767263 |
| Volume | 277 |
| WOSCitedRecordID | wos000180028900095&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LS8QwEB7UFfTia32_chBvcdM0TRsQRIqLB10EPextSdsEVrbt6q6i_94kbfQkHrz00CSlTKczk8zM9wGcCSVUmGiOuVASM6UinHBNMSdUGoceEN3gzN7Fg0EyHIqHBbj0vTC2rNLbRGeoizq3Z-Q942d5THl4NX3BljPK5lZbAo1F6IQmkLE6HQ9_sMJN7Nvw5dkiBBolHrIxZr3nLL9I7XkKCykhvweXzsn01__3ehuw1gaX6LrRhk1YUNUWdK8rs7EuP9E5cuWe7hx9C1ZST_XWhc_7umhpvFCtkaVOKLO6tDfHFfY8uXNkmyDev6c5ej_kgB7GFUpRS_mDPOeKsR0TpD7aSlu3xDzHdnxN7MhjKYvZNjz1b57SW9xyMuCcxdEcaya5YqESsiBUCx1nWodEKM6yMBMRlUUgCZdFrIz14iZ8iQIltAVdLRKVR3QHlqq6UnuA8ig3A5rFoc4Yy4uM2Onapg1JoHW2D6de0iMjDpvHkJWq32YjL-t92G0-1mjaIHOMArc_DaKDP9cewqrndaHkCDra_OzqGJbz9_l49nriNMlcBw_3X_8f1qY |
| 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=Modulation+of+thrombomodulin-dependent+activation+of+human+protein+C+through+differential+expression+of+endothelial+Smads&rft.jtitle=The+Journal+of+biological+chemistry&rft.au=Sandusky%2C+George&rft.au=Berg%2C+David+T&rft.au=Richardson%2C+Mark+A&rft.au=Myers%2C+Laura&rft.date=2002-12-20&rft.issn=0021-9258&rft.volume=277&rft.issue=51&rft.spage=49815&rft_id=info:doi/10.1074%2Fjbc.C200543200&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0021-9258&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0021-9258&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0021-9258&client=summon |