Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae
Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow. Alt...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-11, Vol.279 (47), p.48794-48800 |
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| creator | Lungu, Andreea O Jin, Zheng-Gen Yamawaki, Hideyuki Tanimoto, Tatsuo Wong, Chelsea Berk, Bradford C |
| description | Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling,
and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular
function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used
immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that
CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae.
Exposure of cultured bovine aortic endothelial cells to 1 μ m CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12
dynes/cm 2 ). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A,
because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo , CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation
at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be
caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect
was similar to that of β-cyclodextrin, a cholesterol-binding molecule, and β-cyclodextrin had a similar inhibitory effect
on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 μg/ml cholesterol blocked the
CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in
caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension. |
| doi_str_mv | 10.1074/jbc.M313897200 |
| format | Article |
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and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular
function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used
immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that
CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae.
Exposure of cultured bovine aortic endothelial cells to 1 μ m CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12
dynes/cm 2 ). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A,
because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo , CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation
at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be
caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect
was similar to that of β-cyclodextrin, a cholesterol-binding molecule, and β-cyclodextrin had a similar inhibitory effect
on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 μg/ml cholesterol blocked the
CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in
caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M313897200</identifier><identifier>PMID: 15383526</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Adenoviridae - genetics ; Animals ; Aorta - metabolism ; beta-Cyclodextrins - pharmacology ; Blotting, Western ; Cattle ; Cell Membrane - metabolism ; Cells, Cultured ; Cholesterol - metabolism ; Cyclic AMP-Dependent Protein Kinases - chemistry ; Cyclosporine - pharmacology ; Detergents - pharmacology ; Endothelium, Vascular - enzymology ; Endothelium, Vascular - metabolism ; Enzyme Activation ; Immunoblotting ; Immunosuppressive Agents - pharmacology ; Kinetics ; Nitric Oxide - metabolism ; Nitric Oxide Synthase - metabolism ; Nitric Oxide Synthase Type III ; Phosphorylation ; Protein-Serine-Threonine Kinases - chemistry ; Proto-Oncogene Proteins - chemistry ; Proto-Oncogene Proteins c-akt ; Rabbits ; Serine - chemistry ; Stress, Mechanical ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2004-11, Vol.279 (47), p.48794-48800</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-7df44e7bb65fc1bfc18d4a2a82f5c8379d120eb613f904075139b7e5f7638a973</citedby><cites>FETCH-LOGICAL-c459t-7df44e7bb65fc1bfc18d4a2a82f5c8379d120eb613f904075139b7e5f7638a973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15383526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lungu, Andreea O</creatorcontrib><creatorcontrib>Jin, Zheng-Gen</creatorcontrib><creatorcontrib>Yamawaki, Hideyuki</creatorcontrib><creatorcontrib>Tanimoto, Tatsuo</creatorcontrib><creatorcontrib>Wong, Chelsea</creatorcontrib><creatorcontrib>Berk, Bradford C</creatorcontrib><title>Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling,
and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular
function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used
immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that
CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae.
Exposure of cultured bovine aortic endothelial cells to 1 μ m CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12
dynes/cm 2 ). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A,
because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo , CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation
at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be
caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect
was similar to that of β-cyclodextrin, a cholesterol-binding molecule, and β-cyclodextrin had a similar inhibitory effect
on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 μg/ml cholesterol blocked the
CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in
caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.</description><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Aorta - metabolism</subject><subject>beta-Cyclodextrins - pharmacology</subject><subject>Blotting, Western</subject><subject>Cattle</subject><subject>Cell Membrane - metabolism</subject><subject>Cells, Cultured</subject><subject>Cholesterol - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - chemistry</subject><subject>Cyclosporine - pharmacology</subject><subject>Detergents - pharmacology</subject><subject>Endothelium, Vascular - enzymology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Enzyme Activation</subject><subject>Immunoblotting</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Kinetics</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nitric Oxide Synthase Type III</subject><subject>Phosphorylation</subject><subject>Protein-Serine-Threonine Kinases - chemistry</subject><subject>Proto-Oncogene Proteins - chemistry</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rabbits</subject><subject>Serine - chemistry</subject><subject>Stress, Mechanical</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFrFTEQxoMo9lm9epQcpLd9JptkkxwfS6uFVg8qeAtJdrabkrd5bvJa380_3ZT3oEcHhmHgN98M8yH0npI1JZJ_und-fcsoU1q2hLxAK0oUa5igv16iFSEtbXQr1Bl6k_M9qcE1fY3OqGCKibZbob_9wceUd2kJM97g63kKLpSMr2J6bLYwBFtgwBtfwoMtIc04jfhyHlKZIAYb8ddQluCb9CcMgL8f5jLZDNgd8CYWqJp3uJ9ShFybFHGf5gJzwXVXbx8gRQtv0avRxgzvTvUc_by6_NF_aW6-fb7uNzeN50KXRg4j5yCd68ToqaupBm5bq9pReMWkHmhLwHWUjZpwIgVl2kkQo-yYslqyc3Rx1N0t6fe-HmS2IXuI0c6Q9tl0knSKEfZfkEolGFekgusj6JeU8wKj2S1ha5eDocQ8mWOqOebZnDrw4aS8d_W1z_jJjQp8PAJTuJsewwLGheQn2JpWasOl4Upqzv4BzISX-Q</recordid><startdate>20041119</startdate><enddate>20041119</enddate><creator>Lungu, Andreea O</creator><creator>Jin, Zheng-Gen</creator><creator>Yamawaki, Hideyuki</creator><creator>Tanimoto, Tatsuo</creator><creator>Wong, Chelsea</creator><creator>Berk, Bradford C</creator><general>American Society for Biochemistry and Molecular Biology</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20041119</creationdate><title>Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae</title><author>Lungu, Andreea O ; Jin, Zheng-Gen ; Yamawaki, Hideyuki ; Tanimoto, Tatsuo ; Wong, Chelsea ; Berk, Bradford C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-7df44e7bb65fc1bfc18d4a2a82f5c8379d120eb613f904075139b7e5f7638a973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Aorta - metabolism</topic><topic>beta-Cyclodextrins - pharmacology</topic><topic>Blotting, Western</topic><topic>Cattle</topic><topic>Cell Membrane - metabolism</topic><topic>Cells, Cultured</topic><topic>Cholesterol - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - chemistry</topic><topic>Cyclosporine - pharmacology</topic><topic>Detergents - pharmacology</topic><topic>Endothelium, Vascular - enzymology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Enzyme Activation</topic><topic>Immunoblotting</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Kinetics</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Nitric Oxide Synthase Type III</topic><topic>Phosphorylation</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Proto-Oncogene Proteins - chemistry</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rabbits</topic><topic>Serine - chemistry</topic><topic>Stress, Mechanical</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lungu, Andreea O</creatorcontrib><creatorcontrib>Jin, Zheng-Gen</creatorcontrib><creatorcontrib>Yamawaki, Hideyuki</creatorcontrib><creatorcontrib>Tanimoto, Tatsuo</creatorcontrib><creatorcontrib>Wong, Chelsea</creatorcontrib><creatorcontrib>Berk, Bradford C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lungu, Andreea O</au><au>Jin, Zheng-Gen</au><au>Yamawaki, Hideyuki</au><au>Tanimoto, Tatsuo</au><au>Wong, Chelsea</au><au>Berk, Bradford C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-11-19</date><risdate>2004</risdate><volume>279</volume><issue>47</issue><spage>48794</spage><epage>48800</epage><pages>48794-48800</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling,
and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular
function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used
immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that
CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae.
Exposure of cultured bovine aortic endothelial cells to 1 μ m CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12
dynes/cm 2 ). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A,
because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo , CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation
at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be
caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect
was similar to that of β-cyclodextrin, a cholesterol-binding molecule, and β-cyclodextrin had a similar inhibitory effect
on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 μg/ml cholesterol blocked the
CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in
caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>15383526</pmid><doi>10.1074/jbc.M313897200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adenoviridae - genetics Animals Aorta - metabolism beta-Cyclodextrins - pharmacology Blotting, Western Cattle Cell Membrane - metabolism Cells, Cultured Cholesterol - metabolism Cyclic AMP-Dependent Protein Kinases - chemistry Cyclosporine - pharmacology Detergents - pharmacology Endothelium, Vascular - enzymology Endothelium, Vascular - metabolism Enzyme Activation Immunoblotting Immunosuppressive Agents - pharmacology Kinetics Nitric Oxide - metabolism Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type III Phosphorylation Protein-Serine-Threonine Kinases - chemistry Proto-Oncogene Proteins - chemistry Proto-Oncogene Proteins c-akt Rabbits Serine - chemistry Stress, Mechanical Time Factors |
| title | Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae |
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