Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription
Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function. To test this hypothesis, mice were...
Gespeichert in:
| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2000-12, Vol.102 (25), p.3104-3110 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3110 |
|---|---|
| container_issue | 25 |
| container_start_page | 3104 |
| container_title | Circulation (New York, N.Y.) |
| container_volume | 102 |
| creator | LAUFS, Ulrich ENDRES, Matthias CUSTODIS, Florian GERTZ, Karen NICKENIG, Georg LIAO, James K BÖHM, Michael |
| description | Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.
To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton. |
| doi_str_mv | 10.1161/01.cir.102.25.3104 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72468563</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>72468563</sourcerecordid><originalsourceid>FETCH-LOGICAL-c556t-5363bc73df371c23ec6512dbd541bbecb83ecdb048102d68ef6b5f4b05bf19bb3</originalsourceid><addsrcrecordid>eNpdkc1u1DAUhS0EokPhBVggCyR2Cf5NMks0KqVSJRCUteWf6xmXjBNsh9L34UHxqBFIrKxrfef4-hyEXlLSUtrRd4S2NqSWEtYy2XJKxCO0oZKJRki-fYw2hJBt03PGztCznG_r2PFePkVnlFJGesI26PfXZZ4T5BymiCePIbqpHGAMesQxlBQsnn4FB3hOk1tsOWHaF0j4LpSDS_quglWXiy4h4pJAlyPEgkPGR3BBF3DY3OMI-wr8BOwBnNH2O06wX0Zd1nfTYcKXN591BryHCNVIx2xTmE_Ac_TE6zHDi_U8R98-XNzsPjbXny6vdu-vGytlVxrJO25sz53nPbWMg-0kZc44KagxYM1Qr5whYqiRuW4A3xnphSHSeLo1hp-jtw--9bM_FshFHUO2MI46wrRk1TPRDbLjFXz9H3g7LSnW3RSjrJdk24sKsQfIpinnBF7NKRx1uleUqFOBilC1u_pSR6aYVKcCq-jV6ryYmt8_ydpYBd6sgM5Wj77mZEP-yw18kIPgfwB4maey</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>212750974</pqid></control><display><type>article</type><title>Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription</title><source>MEDLINE</source><source>American Heart Association Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Journals@Ovid Complete</source><creator>LAUFS, Ulrich ; ENDRES, Matthias ; CUSTODIS, Florian ; GERTZ, Karen ; NICKENIG, Georg ; LIAO, James K ; BÖHM, Michael</creator><creatorcontrib>LAUFS, Ulrich ; ENDRES, Matthias ; CUSTODIS, Florian ; GERTZ, Karen ; NICKENIG, Georg ; LIAO, James K ; BÖHM, Michael</creatorcontrib><description>Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.
To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/01.cir.102.25.3104</identifier><identifier>PMID: 11120702</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Actins - physiology ; Animals ; Biological and medical sciences ; Biological Transport ; Blotting, Northern ; Blotting, Western ; Cattle ; Cell Membrane - enzymology ; Cells, Cultured ; Endothelium, Vascular - cytology ; Endothelium, Vascular - enzymology ; Feedback ; Gene Expression Regulation ; General and cellular metabolism. Vitamins ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Medical sciences ; Mice ; Nitric Oxide Synthase - biosynthesis ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase Type III ; Pharmacology. Drug treatments ; Protein Prenylation ; Reverse Transcriptase Polymerase Chain Reaction ; rho GTP-Binding Proteins - genetics ; rho GTP-Binding Proteins - metabolism ; Transcription, Genetic</subject><ispartof>Circulation (New York, N.Y.), 2000-12, Vol.102 (25), p.3104-3110</ispartof><rights>2001 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Dec 19-Dec 26, 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-5363bc73df371c23ec6512dbd541bbecb83ecdb048102d68ef6b5f4b05bf19bb3</citedby><cites>FETCH-LOGICAL-c556t-5363bc73df371c23ec6512dbd541bbecb83ecdb048102d68ef6b5f4b05bf19bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,3674,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=838584$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11120702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LAUFS, Ulrich</creatorcontrib><creatorcontrib>ENDRES, Matthias</creatorcontrib><creatorcontrib>CUSTODIS, Florian</creatorcontrib><creatorcontrib>GERTZ, Karen</creatorcontrib><creatorcontrib>NICKENIG, Georg</creatorcontrib><creatorcontrib>LIAO, James K</creatorcontrib><creatorcontrib>BÖHM, Michael</creatorcontrib><title>Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.
To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.</description><subject>Actins - physiology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Transport</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Cattle</subject><subject>Cell Membrane - enzymology</subject><subject>Cells, Cultured</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - enzymology</subject><subject>Feedback</subject><subject>Gene Expression Regulation</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Nitric Oxide Synthase - biosynthesis</subject><subject>Nitric Oxide Synthase Type II</subject><subject>Nitric Oxide Synthase Type III</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Prenylation</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>rho GTP-Binding Proteins - genetics</subject><subject>rho GTP-Binding Proteins - metabolism</subject><subject>Transcription, Genetic</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1u1DAUhS0EokPhBVggCyR2Cf5NMks0KqVSJRCUteWf6xmXjBNsh9L34UHxqBFIrKxrfef4-hyEXlLSUtrRd4S2NqSWEtYy2XJKxCO0oZKJRki-fYw2hJBt03PGztCznG_r2PFePkVnlFJGesI26PfXZZ4T5BymiCePIbqpHGAMesQxlBQsnn4FB3hOk1tsOWHaF0j4LpSDS_quglWXiy4h4pJAlyPEgkPGR3BBF3DY3OMI-wr8BOwBnNH2O06wX0Zd1nfTYcKXN591BryHCNVIx2xTmE_Ac_TE6zHDi_U8R98-XNzsPjbXny6vdu-vGytlVxrJO25sz53nPbWMg-0kZc44KagxYM1Qr5whYqiRuW4A3xnphSHSeLo1hp-jtw--9bM_FshFHUO2MI46wrRk1TPRDbLjFXz9H3g7LSnW3RSjrJdk24sKsQfIpinnBF7NKRx1uleUqFOBilC1u_pSR6aYVKcCq-jV6ryYmt8_ydpYBd6sgM5Wj77mZEP-yw18kIPgfwB4maey</recordid><startdate>20001219</startdate><enddate>20001219</enddate><creator>LAUFS, Ulrich</creator><creator>ENDRES, Matthias</creator><creator>CUSTODIS, Florian</creator><creator>GERTZ, Karen</creator><creator>NICKENIG, Georg</creator><creator>LIAO, James K</creator><creator>BÖHM, Michael</creator><general>Lippincott Williams & Wilkins</general><general>American Heart Association, Inc</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>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>20001219</creationdate><title>Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription</title><author>LAUFS, Ulrich ; ENDRES, Matthias ; CUSTODIS, Florian ; GERTZ, Karen ; NICKENIG, Georg ; LIAO, James K ; BÖHM, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c556t-5363bc73df371c23ec6512dbd541bbecb83ecdb048102d68ef6b5f4b05bf19bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Actins - physiology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Transport</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Cattle</topic><topic>Cell Membrane - enzymology</topic><topic>Cells, Cultured</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - enzymology</topic><topic>Feedback</topic><topic>Gene Expression Regulation</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Nitric Oxide Synthase - biosynthesis</topic><topic>Nitric Oxide Synthase Type II</topic><topic>Nitric Oxide Synthase Type III</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Prenylation</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>rho GTP-Binding Proteins - genetics</topic><topic>rho GTP-Binding Proteins - metabolism</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LAUFS, Ulrich</creatorcontrib><creatorcontrib>ENDRES, Matthias</creatorcontrib><creatorcontrib>CUSTODIS, Florian</creatorcontrib><creatorcontrib>GERTZ, Karen</creatorcontrib><creatorcontrib>NICKENIG, Georg</creatorcontrib><creatorcontrib>LIAO, James K</creatorcontrib><creatorcontrib>BÖHM, Michael</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>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LAUFS, Ulrich</au><au>ENDRES, Matthias</au><au>CUSTODIS, Florian</au><au>GERTZ, Karen</au><au>NICKENIG, Georg</au><au>LIAO, James K</au><au>BÖHM, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2000-12-19</date><risdate>2000</risdate><volume>102</volume><issue>25</issue><spage>3104</spage><epage>3110</epage><pages>3104-3110</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.
To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>11120702</pmid><doi>10.1161/01.cir.102.25.3104</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-7322 |
| ispartof | Circulation (New York, N.Y.), 2000-12, Vol.102 (25), p.3104-3110 |
| issn | 0009-7322 1524-4539 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72468563 |
| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete |
| subjects | Actins - physiology Animals Biological and medical sciences Biological Transport Blotting, Northern Blotting, Western Cattle Cell Membrane - enzymology Cells, Cultured Endothelium, Vascular - cytology Endothelium, Vascular - enzymology Feedback Gene Expression Regulation General and cellular metabolism. Vitamins Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Medical sciences Mice Nitric Oxide Synthase - biosynthesis Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Pharmacology. Drug treatments Protein Prenylation Reverse Transcriptase Polymerase Chain Reaction rho GTP-Binding Proteins - genetics rho GTP-Binding Proteins - metabolism Transcription, Genetic |
| title | Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T20%3A30%3A19IST&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=Suppression%20of%20endothelial%20nitric%20oxide%20production%20after%20withdrawal%20of%20statin%20treatment%20is%20mediated%20by%20negative%20feedback%20regulation%20of%20rho%20GTPase%20gene%20transcription&rft.jtitle=Circulation%20(New%20York,%20N.Y.)&rft.au=LAUFS,%20Ulrich&rft.date=2000-12-19&rft.volume=102&rft.issue=25&rft.spage=3104&rft.epage=3110&rft.pages=3104-3110&rft.issn=0009-7322&rft.eissn=1524-4539&rft.coden=CIRCAZ&rft_id=info:doi/10.1161/01.cir.102.25.3104&rft_dat=%3Cproquest_cross%3E72468563%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=212750974&rft_id=info:pmid/11120702&rfr_iscdi=true |