Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction
OBJECTIVE—We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia. METHODS AND RESULTS—Mice that were wild type (Gpx1), heterozygous (Gpx1), or homozygous (Gpx1) for the mutated...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2002-12, Vol.22 (12), p.1996-2002 |
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| container_end_page | 2002 |
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| container_issue | 12 |
| container_start_page | 1996 |
| container_title | Arteriosclerosis, thrombosis, and vascular biology |
| container_volume | 22 |
| creator | Dayal, Sanjana Brown, Kara L Weydert, Christine J Oberley, Larry W Arning, Erland Bottiglieri, Teodoro Faraci, Frank M Lentz, Steven R |
| description | OBJECTIVE—We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia.
METHODS AND RESULTS—Mice that were wild type (Gpx1), heterozygous (Gpx1), or homozygous (Gpx1) for the mutated Gpx1 allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma total homocysteine was elevated in mice on the high-methionine diet compared with mice on the control diet (23±3 versus 6±0.3 μmol/L, respectively;P |
| doi_str_mv | 10.1161/01.ATV.0000041629.92741.DC |
| format | Article |
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METHODS AND RESULTS—Mice that were wild type (Gpx1), heterozygous (Gpx1), or homozygous (Gpx1) for the mutated Gpx1 allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma total homocysteine was elevated in mice on the high-methionine diet compared with mice on the control diet (23±3 versus 6±0.3 μmol/L, respectively;P <0.001) and was not influenced by Gpx1 genotype. In mice fed the control diet, maximal relaxation of the aorta in response to the endothelium-dependent dilator acetylcholine (10 mol/L) was similar in Gpx1, Gpx1, and Gpx1 mice, but relaxation to lower concentrations of acetylcholine was selectively impaired in Gpx1 mice (P <0.05 versus Gpx1 mice). In mice fed the high-methionine diet, relaxation to low and high concentrations of acetylcholine was impaired in Gpx1 mice (maximal relaxation 73±6% in Gpx1 mice versus 90±2% in Gpx1 mice, P <0.05). No differences in vasorelaxation to nitroprusside or papaverine were observed between Gpx1 and Gpx1 mice fed either diet. Dihydroethidium fluorescence, a marker of superoxide, was elevated in Gpx1 mice fed the high-methionine diet (P <0.05 versus Gpx1 mice fed the control diet).
CONCLUSIONS—These findings demonstrate that deficiency of GPx-1 exacerbates endothelial dysfunction in hyperhomocysteinemic mice and provide support for the hypothesis that hyperhomocysteinemia contributes to endothelial dysfunction through a peroxide-dependent oxidative mechanism.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/01.ATV.0000041629.92741.DC</identifier><identifier>PMID: 12482825</identifier><identifier>CODEN: ATVBFA</identifier><language>eng</language><publisher>Philadelphia, PA: American Heart Association, Inc</publisher><subject>Animals ; Aorta, Thoracic - drug effects ; Aorta, Thoracic - enzymology ; Biological and medical sciences ; Cardiology. Vascular system ; Carotid Arteries - chemistry ; Carotid Arteries - drug effects ; Carotid Arteries - enzymology ; Catalase - metabolism ; Coronary heart disease ; Diet ; Endothelium, Vascular - enzymology ; Endothelium, Vascular - physiopathology ; Ethidium - analogs & derivatives ; Ethidium - analysis ; Glutathione Peroxidase - blood ; Glutathione Peroxidase - deficiency ; Glutathione Peroxidase - genetics ; Heart ; Homocysteine - blood ; Hyperhomocysteinemia - blood ; Hyperhomocysteinemia - enzymology ; Hyperhomocysteinemia - genetics ; Liver - enzymology ; Medical sciences ; Methionine - blood ; Methionine - metabolism ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; Mice, Knockout ; Superoxide Dismutase - metabolism ; Superoxides - analysis ; Vasomotor System - drug effects ; Vasomotor System - enzymology</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2002-12, Vol.22 (12), p.1996-2002</ispartof><rights>2002 American Heart Association, Inc.</rights><rights>2003 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Dec 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5042-4278411e0a3fc126da161a733942ab3006044cef2c40ba1f10d53ebd6f6304f53</citedby><cites>FETCH-LOGICAL-c5042-4278411e0a3fc126da161a733942ab3006044cef2c40ba1f10d53ebd6f6304f53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14430243$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12482825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dayal, Sanjana</creatorcontrib><creatorcontrib>Brown, Kara L</creatorcontrib><creatorcontrib>Weydert, Christine J</creatorcontrib><creatorcontrib>Oberley, Larry W</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Faraci, Frank M</creatorcontrib><creatorcontrib>Lentz, Steven R</creatorcontrib><title>Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>OBJECTIVE—We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia.
METHODS AND RESULTS—Mice that were wild type (Gpx1), heterozygous (Gpx1), or homozygous (Gpx1) for the mutated Gpx1 allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma total homocysteine was elevated in mice on the high-methionine diet compared with mice on the control diet (23±3 versus 6±0.3 μmol/L, respectively;P <0.001) and was not influenced by Gpx1 genotype. In mice fed the control diet, maximal relaxation of the aorta in response to the endothelium-dependent dilator acetylcholine (10 mol/L) was similar in Gpx1, Gpx1, and Gpx1 mice, but relaxation to lower concentrations of acetylcholine was selectively impaired in Gpx1 mice (P <0.05 versus Gpx1 mice). In mice fed the high-methionine diet, relaxation to low and high concentrations of acetylcholine was impaired in Gpx1 mice (maximal relaxation 73±6% in Gpx1 mice versus 90±2% in Gpx1 mice, P <0.05). No differences in vasorelaxation to nitroprusside or papaverine were observed between Gpx1 and Gpx1 mice fed either diet. Dihydroethidium fluorescence, a marker of superoxide, was elevated in Gpx1 mice fed the high-methionine diet (P <0.05 versus Gpx1 mice fed the control diet).
CONCLUSIONS—These findings demonstrate that deficiency of GPx-1 exacerbates endothelial dysfunction in hyperhomocysteinemic mice and provide support for the hypothesis that hyperhomocysteinemia contributes to endothelial dysfunction through a peroxide-dependent oxidative mechanism.</description><subject>Animals</subject><subject>Aorta, Thoracic - drug effects</subject><subject>Aorta, Thoracic - enzymology</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Carotid Arteries - chemistry</subject><subject>Carotid Arteries - drug effects</subject><subject>Carotid Arteries - enzymology</subject><subject>Catalase - metabolism</subject><subject>Coronary heart disease</subject><subject>Diet</subject><subject>Endothelium, Vascular - enzymology</subject><subject>Endothelium, Vascular - physiopathology</subject><subject>Ethidium - analogs & derivatives</subject><subject>Ethidium - analysis</subject><subject>Glutathione Peroxidase - blood</subject><subject>Glutathione Peroxidase - deficiency</subject><subject>Glutathione Peroxidase - genetics</subject><subject>Heart</subject><subject>Homocysteine - blood</subject><subject>Hyperhomocysteinemia - blood</subject><subject>Hyperhomocysteinemia - enzymology</subject><subject>Hyperhomocysteinemia - genetics</subject><subject>Liver - enzymology</subject><subject>Medical sciences</subject><subject>Methionine - blood</subject><subject>Methionine - metabolism</subject><subject>Mice</subject><subject>Mice, Congenic</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Superoxides - analysis</subject><subject>Vasomotor System - drug effects</subject><subject>Vasomotor System - enzymology</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkVFv0zAUhSMEYmPwF1A0ib0l2Nc3Tsvb1I4NaQgkBq-W61yrHklcbEcj_HpcWqkSluzrh--ec-1TFJec1ZxL_p7x-vrhR832C7mEZb2EFnm9Xj0rznkDWKEU8nm-s3ZZNRLhrHgV4-MeB2AvizMOuIAFNOeFXZN1xtFo5tLb8rafkk5b50cqv1Lwv12nI1W8_EZjdMn9oVjezTsKWz94M8dEbqTBmfKzM1QmX96MnU9b6p3uy_Uc7TSalNVeFy-s7iO9OdaL4vvHm4fVXXX_5fbT6vq-Mk2erUJoF8g5MS2s4SA7nd-rWyGWCHojGJMM0ZAFg2yjueWsawRtOmmlYGgbcVFcHXR3wf-aKCY1uGio7_VIfoqqhbbFFiGDl_-Bj34KY55NAcMslq0y9OEAmeBjDGTVLrhBh1lxpvZRKMZVjkKdolD_olDrVW5-e3SYNgN1p9bj32fg3RHQ0ejeBj0aF08c5jEARebwwD35PlGIP_vpiYLaku7Tdm-NQrKmAsaA54NVeXMQfwEdqKGC</recordid><startdate>200212</startdate><enddate>200212</enddate><creator>Dayal, Sanjana</creator><creator>Brown, Kara L</creator><creator>Weydert, Christine J</creator><creator>Oberley, Larry W</creator><creator>Arning, Erland</creator><creator>Bottiglieri, Teodoro</creator><creator>Faraci, Frank M</creator><creator>Lentz, Steven R</creator><general>American Heart Association, Inc</general><general>Lippincott</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>7X8</scope></search><sort><creationdate>200212</creationdate><title>Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction</title><author>Dayal, Sanjana ; Brown, Kara L ; Weydert, Christine J ; Oberley, Larry W ; Arning, Erland ; Bottiglieri, Teodoro ; Faraci, Frank M ; Lentz, Steven R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5042-4278411e0a3fc126da161a733942ab3006044cef2c40ba1f10d53ebd6f6304f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Aorta, Thoracic - drug effects</topic><topic>Aorta, Thoracic - enzymology</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Carotid Arteries - chemistry</topic><topic>Carotid Arteries - drug effects</topic><topic>Carotid Arteries - enzymology</topic><topic>Catalase - metabolism</topic><topic>Coronary heart disease</topic><topic>Diet</topic><topic>Endothelium, Vascular - enzymology</topic><topic>Endothelium, Vascular - physiopathology</topic><topic>Ethidium - analogs & derivatives</topic><topic>Ethidium - analysis</topic><topic>Glutathione Peroxidase - blood</topic><topic>Glutathione Peroxidase - deficiency</topic><topic>Glutathione Peroxidase - genetics</topic><topic>Heart</topic><topic>Homocysteine - blood</topic><topic>Hyperhomocysteinemia - blood</topic><topic>Hyperhomocysteinemia - enzymology</topic><topic>Hyperhomocysteinemia - genetics</topic><topic>Liver - enzymology</topic><topic>Medical sciences</topic><topic>Methionine - blood</topic><topic>Methionine - metabolism</topic><topic>Mice</topic><topic>Mice, Congenic</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Superoxides - analysis</topic><topic>Vasomotor System - drug effects</topic><topic>Vasomotor System - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dayal, Sanjana</creatorcontrib><creatorcontrib>Brown, Kara L</creatorcontrib><creatorcontrib>Weydert, Christine J</creatorcontrib><creatorcontrib>Oberley, Larry W</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Faraci, Frank M</creatorcontrib><creatorcontrib>Lentz, Steven R</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>MEDLINE - Academic</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dayal, Sanjana</au><au>Brown, Kara L</au><au>Weydert, Christine J</au><au>Oberley, Larry W</au><au>Arning, Erland</au><au>Bottiglieri, Teodoro</au><au>Faraci, Frank M</au><au>Lentz, Steven R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2002-12</date><risdate>2002</risdate><volume>22</volume><issue>12</issue><spage>1996</spage><epage>2002</epage><pages>1996-2002</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><coden>ATVBFA</coden><abstract>OBJECTIVE—We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia.
METHODS AND RESULTS—Mice that were wild type (Gpx1), heterozygous (Gpx1), or homozygous (Gpx1) for the mutated Gpx1 allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma total homocysteine was elevated in mice on the high-methionine diet compared with mice on the control diet (23±3 versus 6±0.3 μmol/L, respectively;P <0.001) and was not influenced by Gpx1 genotype. In mice fed the control diet, maximal relaxation of the aorta in response to the endothelium-dependent dilator acetylcholine (10 mol/L) was similar in Gpx1, Gpx1, and Gpx1 mice, but relaxation to lower concentrations of acetylcholine was selectively impaired in Gpx1 mice (P <0.05 versus Gpx1 mice). In mice fed the high-methionine diet, relaxation to low and high concentrations of acetylcholine was impaired in Gpx1 mice (maximal relaxation 73±6% in Gpx1 mice versus 90±2% in Gpx1 mice, P <0.05). No differences in vasorelaxation to nitroprusside or papaverine were observed between Gpx1 and Gpx1 mice fed either diet. Dihydroethidium fluorescence, a marker of superoxide, was elevated in Gpx1 mice fed the high-methionine diet (P <0.05 versus Gpx1 mice fed the control diet).
CONCLUSIONS—These findings demonstrate that deficiency of GPx-1 exacerbates endothelial dysfunction in hyperhomocysteinemic mice and provide support for the hypothesis that hyperhomocysteinemia contributes to endothelial dysfunction through a peroxide-dependent oxidative mechanism.</abstract><cop>Philadelphia, PA</cop><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>12482825</pmid><doi>10.1161/01.ATV.0000041629.92741.DC</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1079-5642 |
| ispartof | Arteriosclerosis, thrombosis, and vascular biology, 2002-12, Vol.22 (12), p.1996-2002 |
| issn | 1079-5642 1524-4636 |
| language | eng |
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| source | MEDLINE; Journals@Ovid Complete; Alma/SFX Local Collection |
| subjects | Animals Aorta, Thoracic - drug effects Aorta, Thoracic - enzymology Biological and medical sciences Cardiology. Vascular system Carotid Arteries - chemistry Carotid Arteries - drug effects Carotid Arteries - enzymology Catalase - metabolism Coronary heart disease Diet Endothelium, Vascular - enzymology Endothelium, Vascular - physiopathology Ethidium - analogs & derivatives Ethidium - analysis Glutathione Peroxidase - blood Glutathione Peroxidase - deficiency Glutathione Peroxidase - genetics Heart Homocysteine - blood Hyperhomocysteinemia - blood Hyperhomocysteinemia - enzymology Hyperhomocysteinemia - genetics Liver - enzymology Medical sciences Methionine - blood Methionine - metabolism Mice Mice, Congenic Mice, Inbred C57BL Mice, Knockout Superoxide Dismutase - metabolism Superoxides - analysis Vasomotor System - drug effects Vasomotor System - enzymology |
| title | Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction |
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