Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact of statins on production of reactive oxygen spe...
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| Veröffentlicht in: | Molecular pharmacology 2001-03, Vol.59 (3), p.646-654 |
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| creator | Wassmann, S Laufs, U Bäumer, A T Müller, K Konkol, C Sauer, H Böhm, M Nickenig, G |
| description | 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent
of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact
of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC
to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited
angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent
manner and consistently reduced AT1 receptor density. l -Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels.
Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor
gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor
mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity,
and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1
activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused
down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent
down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates
a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma
cholesterol. |
| doi_str_mv | 10.1124/mol.59.3.646 |
| format | Article |
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of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact
of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC
to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited
angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent
manner and consistently reduced AT1 receptor density. l -Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels.
Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor
gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor
mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity,
and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1
activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused
down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent
down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates
a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma
cholesterol.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.59.3.646</identifier><identifier>PMID: 11179461</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Angiotensin II - drug effects ; Angiotensin II - physiology ; Animals ; Atorvastatin ; Cells, Cultured ; Down-Regulation ; Free Radicals - metabolism ; Gene Expression - drug effects ; GTP Phosphohydrolases - physiology ; Heptanoic Acids - pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Male ; Muscle, Smooth, Vascular - metabolism ; Protein Prenylation ; Pyrroles - pharmacology ; rac1 GTP-Binding Protein - antagonists & inhibitors ; rac1 GTP-Binding Protein - metabolism ; Radioligand Assay ; Rats ; Rats, Inbred SHR ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; Receptor, Angiotensin, Type 2 ; Receptors, Angiotensin - biosynthesis ; Receptors, Angiotensin - genetics ; Receptors, Angiotensin - physiology ; RNA Stability - drug effects ; RNA, Messenger - drug effects ; RNA, Messenger - metabolism</subject><ispartof>Molecular pharmacology, 2001-03, Vol.59 (3), p.646-654</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-52a07c0ce0283ca210ac35870693e77096382bbc88b3406d2ff4c2f8f02ad2813</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11179461$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wassmann, S</creatorcontrib><creatorcontrib>Laufs, U</creatorcontrib><creatorcontrib>Bäumer, A T</creatorcontrib><creatorcontrib>Müller, K</creatorcontrib><creatorcontrib>Konkol, C</creatorcontrib><creatorcontrib>Sauer, H</creatorcontrib><creatorcontrib>Böhm, M</creatorcontrib><creatorcontrib>Nickenig, G</creatorcontrib><title>Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent
of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact
of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC
to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited
angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent
manner and consistently reduced AT1 receptor density. l -Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels.
Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor
gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor
mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity,
and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1
activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused
down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent
down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates
a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma
cholesterol.</description><subject>Angiotensin II - drug effects</subject><subject>Angiotensin II - physiology</subject><subject>Animals</subject><subject>Atorvastatin</subject><subject>Cells, Cultured</subject><subject>Down-Regulation</subject><subject>Free Radicals - metabolism</subject><subject>Gene Expression - drug effects</subject><subject>GTP Phosphohydrolases - physiology</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Male</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Protein Prenylation</subject><subject>Pyrroles - pharmacology</subject><subject>rac1 GTP-Binding Protein - antagonists & inhibitors</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Inbred SHR</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Angiotensin, Type 1</subject><subject>Receptor, Angiotensin, Type 2</subject><subject>Receptors, Angiotensin - biosynthesis</subject><subject>Receptors, Angiotensin - genetics</subject><subject>Receptors, Angiotensin - physiology</subject><subject>RNA Stability - drug effects</subject><subject>RNA, Messenger - drug effects</subject><subject>RNA, Messenger - metabolism</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkc1u1DAUhSMEokNhxxp5Aysy-Cc_DrvRqB0itaIqA2JnOc7NxMixUzspnYfru-HpjFRWV7I_f0fXJ0neE7wkhGZfBmeWebVkyyIrXiQLklOSYkLIy2SBMS1SXuW_z5I3IfzBmGQ5x6-Ts3hdVllBFsljbXvd6Ek7i1yHNuCl3Zvdccin41toZwUBrexOuwls0BbVdXoNrZYTtOjSA6Bb2WolDbrxLtJP7yL2SwY1G-nRj8G5qUfXc1AG0BqMCV9Rbe-duYcB7HTI_t-_2pKYq2CcnEcXD6OHEA5OadsYpQjabG9kgLfJq06aAO9O8zz5eXmxXX9Lr75v6vXqKlWMsynNqcSlwgow5UxJSrBULOclLioGZYmrgnHaNIrzhmW4aGnXZYp2vMNUtpQTdp58OnpH7-5mCJMYdFBxC2nBzUFEE6PxeyP4-Qgq70Lw0InR60H6vSBYHOoSsS6RV4KJWFfEP5y8czNA-wyf-onAxyPQ613_V3sQYy_9IJUzbrd_Fv0DEziggA</recordid><startdate>20010301</startdate><enddate>20010301</enddate><creator>Wassmann, S</creator><creator>Laufs, U</creator><creator>Bäumer, A T</creator><creator>Müller, K</creator><creator>Konkol, C</creator><creator>Sauer, H</creator><creator>Böhm, M</creator><creator>Nickenig, G</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><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>7X8</scope></search><sort><creationdate>20010301</creationdate><title>Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase</title><author>Wassmann, S ; Laufs, U ; Bäumer, A T ; Müller, K ; Konkol, C ; Sauer, H ; Böhm, M ; Nickenig, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-52a07c0ce0283ca210ac35870693e77096382bbc88b3406d2ff4c2f8f02ad2813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Angiotensin II - drug effects</topic><topic>Angiotensin II - physiology</topic><topic>Animals</topic><topic>Atorvastatin</topic><topic>Cells, Cultured</topic><topic>Down-Regulation</topic><topic>Free Radicals - metabolism</topic><topic>Gene Expression - drug effects</topic><topic>GTP Phosphohydrolases - physiology</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Male</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Protein Prenylation</topic><topic>Pyrroles - pharmacology</topic><topic>rac1 GTP-Binding Protein - antagonists & inhibitors</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Inbred SHR</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Angiotensin, Type 1</topic><topic>Receptor, Angiotensin, Type 2</topic><topic>Receptors, Angiotensin - biosynthesis</topic><topic>Receptors, Angiotensin - genetics</topic><topic>Receptors, Angiotensin - physiology</topic><topic>RNA Stability - drug effects</topic><topic>RNA, Messenger - drug effects</topic><topic>RNA, Messenger - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wassmann, S</creatorcontrib><creatorcontrib>Laufs, U</creatorcontrib><creatorcontrib>Bäumer, A T</creatorcontrib><creatorcontrib>Müller, K</creatorcontrib><creatorcontrib>Konkol, C</creatorcontrib><creatorcontrib>Sauer, H</creatorcontrib><creatorcontrib>Böhm, M</creatorcontrib><creatorcontrib>Nickenig, G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wassmann, S</au><au>Laufs, U</au><au>Bäumer, A T</au><au>Müller, K</au><au>Konkol, C</au><au>Sauer, H</au><au>Böhm, M</au><au>Nickenig, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>2001-03-01</date><risdate>2001</risdate><volume>59</volume><issue>3</issue><spage>646</spage><epage>654</epage><pages>646-654</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent
of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact
of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC
to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited
angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent
manner and consistently reduced AT1 receptor density. l -Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels.
Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor
gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor
mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity,
and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1
activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused
down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent
down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates
a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma
cholesterol.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>11179461</pmid><doi>10.1124/mol.59.3.646</doi><tpages>9</tpages></addata></record> |
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| ispartof | Molecular pharmacology, 2001-03, Vol.59 (3), p.646-654 |
| issn | 0026-895X 1521-0111 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Angiotensin II - drug effects Angiotensin II - physiology Animals Atorvastatin Cells, Cultured Down-Regulation Free Radicals - metabolism Gene Expression - drug effects GTP Phosphohydrolases - physiology Heptanoic Acids - pharmacology Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Male Muscle, Smooth, Vascular - metabolism Protein Prenylation Pyrroles - pharmacology rac1 GTP-Binding Protein - antagonists & inhibitors rac1 GTP-Binding Protein - metabolism Radioligand Assay Rats Rats, Inbred SHR Rats, Sprague-Dawley Receptor, Angiotensin, Type 1 Receptor, Angiotensin, Type 2 Receptors, Angiotensin - biosynthesis Receptors, Angiotensin - genetics Receptors, Angiotensin - physiology RNA Stability - drug effects RNA, Messenger - drug effects RNA, Messenger - metabolism |
| title | Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase |
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