HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis
Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) c...
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| Veröffentlicht in: | Cardiovascular research 2012-07, Vol.95 (1), p.116-123 |
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| creator | MADRIGAL-MATUTE, Julio FERNANDEZ-GARCIA, Carlos Ernesto GOMEZ-GUERRERO, Carmen LOPEZ-FRANCO, Oscar MUNOZ-GARCIA, Begona EGIDO, Jesus MIGUEL BLANCO-COLIO, Luis MARTIN-VENTURA, Jose Luis |
| description | Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.
Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.
Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors. |
| doi_str_mv | 10.1093/cvr/cvs158 |
| format | Article |
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Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.
Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvs158</identifier><identifier>PMID: 22547655</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animals ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - metabolism ; Benzoquinones - pharmacology ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cell Differentiation ; Extracellular Signal-Regulated MAP Kinases - metabolism ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; Lactams, Macrocyclic - pharmacology ; Macrophages - cytology ; Male ; Medical sciences ; Mice ; Muscle, Smooth, Vascular - drug effects ; NADPH Oxidases - metabolism ; Oxidative Stress - drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species - metabolism</subject><ispartof>Cardiovascular research, 2012-07, Vol.95 (1), p.116-123</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-f8df6e467601e5fc88b2be15e96ef6566dafe16d1948e46fc008d48d8eee3703</citedby><cites>FETCH-LOGICAL-c419t-f8df6e467601e5fc88b2be15e96ef6566dafe16d1948e46fc008d48d8eee3703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26016204$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22547655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MADRIGAL-MATUTE, Julio</creatorcontrib><creatorcontrib>FERNANDEZ-GARCIA, Carlos Ernesto</creatorcontrib><creatorcontrib>GOMEZ-GUERRERO, Carmen</creatorcontrib><creatorcontrib>LOPEZ-FRANCO, Oscar</creatorcontrib><creatorcontrib>MUNOZ-GARCIA, Begona</creatorcontrib><creatorcontrib>EGIDO, Jesus</creatorcontrib><creatorcontrib>MIGUEL BLANCO-COLIO, Luis</creatorcontrib><creatorcontrib>MARTIN-VENTURA, Jose Luis</creatorcontrib><title>HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.
Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.
Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.</description><subject>Animals</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Atherosclerosis - metabolism</subject><subject>Benzoquinones - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cell Differentiation</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>Lactams, Macrocyclic - pharmacology</subject><subject>Macrophages - cytology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>NADPH Oxidases - metabolism</subject><subject>Oxidative Stress - drug effects</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reactive Oxygen Species - metabolism</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0F1LwzAUBuAgipsfN_4A6Y0gQjVp89XLMXUTJgoOvCxpesIiXTuTdGz_3oxNvUjCgSeHc16Ergi-J7jIH_TaxeMJk0doSARjaZ5RdoyGGGOZ8pznA3Tm_VcsGRP0FA2yjFHBGRuiz-nHe4ET2y5sZYPt2qTaJkSkj6-jSaJCgLZXAXzSbWytgl1D4oMD7-OPBDYrcHYJbVBNtAtwndfN7rb-Ap0Y1Xi4PLznaP78NB9P09nb5GU8mqWakiKkRtaGA-WCYwLMaCmrrALCoOBgOOO8VgYIr0lBZWRGx41qKmsJALnA-Tm63bddue67Bx_KpfUamka10PW-JDgjhSiEEJHe7amOA3oHplzF4ZXbRlTucixjjuU-x4ivD337agn1H_0NLoKbA1Beq8Y41Wrr_13ch2eY5j9CrnyU</recordid><startdate>20120701</startdate><enddate>20120701</enddate><creator>MADRIGAL-MATUTE, Julio</creator><creator>FERNANDEZ-GARCIA, Carlos Ernesto</creator><creator>GOMEZ-GUERRERO, Carmen</creator><creator>LOPEZ-FRANCO, Oscar</creator><creator>MUNOZ-GARCIA, Begona</creator><creator>EGIDO, Jesus</creator><creator>MIGUEL BLANCO-COLIO, Luis</creator><creator>MARTIN-VENTURA, Jose Luis</creator><general>Oxford University Press</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>7X8</scope></search><sort><creationdate>20120701</creationdate><title>HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis</title><author>MADRIGAL-MATUTE, Julio ; FERNANDEZ-GARCIA, Carlos Ernesto ; GOMEZ-GUERRERO, Carmen ; LOPEZ-FRANCO, Oscar ; MUNOZ-GARCIA, Begona ; EGIDO, Jesus ; MIGUEL BLANCO-COLIO, Luis ; MARTIN-VENTURA, Jose Luis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-f8df6e467601e5fc88b2be15e96ef6566dafe16d1948e46fc008d48d8eee3703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Atherosclerosis - metabolism</topic><topic>Benzoquinones - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cell Differentiation</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>Lactams, Macrocyclic - pharmacology</topic><topic>Macrophages - cytology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>NADPH Oxidases - metabolism</topic><topic>Oxidative Stress - drug effects</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Reactive Oxygen Species - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MADRIGAL-MATUTE, Julio</creatorcontrib><creatorcontrib>FERNANDEZ-GARCIA, Carlos Ernesto</creatorcontrib><creatorcontrib>GOMEZ-GUERRERO, Carmen</creatorcontrib><creatorcontrib>LOPEZ-FRANCO, Oscar</creatorcontrib><creatorcontrib>MUNOZ-GARCIA, Begona</creatorcontrib><creatorcontrib>EGIDO, Jesus</creatorcontrib><creatorcontrib>MIGUEL BLANCO-COLIO, Luis</creatorcontrib><creatorcontrib>MARTIN-VENTURA, Jose Luis</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>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MADRIGAL-MATUTE, Julio</au><au>FERNANDEZ-GARCIA, Carlos Ernesto</au><au>GOMEZ-GUERRERO, Carmen</au><au>LOPEZ-FRANCO, Oscar</au><au>MUNOZ-GARCIA, Begona</au><au>EGIDO, Jesus</au><au>MIGUEL BLANCO-COLIO, Luis</au><au>MARTIN-VENTURA, Jose Luis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2012-07-01</date><risdate>2012</risdate><volume>95</volume><issue>1</issue><spage>116</spage><epage>123</epage><pages>116-123</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.
Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.
Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>22547655</pmid><doi>10.1093/cvr/cvs158</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Atherosclerosis (general aspects, experimental research) Atherosclerosis - metabolism Benzoquinones - pharmacology Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cell Differentiation Extracellular Signal-Regulated MAP Kinases - metabolism HSP90 Heat-Shock Proteins - antagonists & inhibitors Lactams, Macrocyclic - pharmacology Macrophages - cytology Male Medical sciences Mice Muscle, Smooth, Vascular - drug effects NADPH Oxidases - metabolism Oxidative Stress - drug effects Rats Rats, Wistar Reactive Oxygen Species - metabolism |
| title | HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis |
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