Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice
Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine...
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| Veröffentlicht in: | Circulation research 2001-06, Vol.88 (11), p.1203-1209 |
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| container_title | Circulation research |
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| creator | Dayal, Sanjana Bottiglieri, Teodoro Arning, Erland Maeda, Nobuyo Malinow, M René Sigmund, Curt D Heistad, Donald D Faraci, Frank M Lentz, Steven R |
| description | Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS) and wild-type (CBS) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS mice compared with CBS mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L;P |
| doi_str_mv | 10.1161/hh1101.092180 |
| format | Article |
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Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS) and wild-type (CBS) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS mice compared with CBS mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L;P <0.001) and 15 weeks (23.9±3.0 versus 13.0±2.3 μmol/L;P <0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% (P <0.05) and thrombomodulin anticoagulant activity was decreased by 20% (P <0.05) in CBS mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS mice, and correlations were observed between plasma total homocysteine and SAH in liver (r =0.54;P <0.001) and brain (r =0.67;P <0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.]]></description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/hh1101.092180</identifier><identifier>PMID: 11397788</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Aminoacid disorders ; Animals ; Aorta - drug effects ; Aorta - metabolism ; Aorta - physiopathology ; Biological and medical sciences ; Brain - metabolism ; Chronic Disease ; Cystathionine beta-Synthase - deficiency ; Cystathionine beta-Synthase - genetics ; Disease Models, Animal ; Endothelium, Vascular - physiopathology ; Errors of metabolism ; Folic Acid - blood ; Food, Fortified ; Heterozygote ; Homocysteine - blood ; Hyperhomocysteinemia - blood ; Hyperhomocysteinemia - physiopathology ; In Vitro Techniques ; Liver - metabolism ; Medical sciences ; Metabolic diseases ; Methionine - blood ; Methylation ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; S-Adenosylhomocysteine - metabolism ; S-Adenosylmethionine - metabolism ; Thrombomodulin - metabolism ; Vasoconstrictor Agents - pharmacology ; Vasodilator Agents - pharmacology ; Vasomotor System - drug effects ; Vasomotor System - physiopathology</subject><ispartof>Circulation research, 2001-06, Vol.88 (11), p.1203-1209</ispartof><rights>2001 American Heart Association, Inc.</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4028-8d8fec7b23ca7cdb1226943bf8a4f0927959ac6177422cdf7add25958bd584f93</citedby><cites>FETCH-LOGICAL-c4028-8d8fec7b23ca7cdb1226943bf8a4f0927959ac6177422cdf7add25958bd584f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1043114$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11397788$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dayal, Sanjana</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Maeda, Nobuyo</creatorcontrib><creatorcontrib>Malinow, M René</creatorcontrib><creatorcontrib>Sigmund, Curt D</creatorcontrib><creatorcontrib>Heistad, Donald D</creatorcontrib><creatorcontrib>Faraci, Frank M</creatorcontrib><creatorcontrib>Lentz, Steven R</creatorcontrib><title>Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description><![CDATA[Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS) and wild-type (CBS) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS mice compared with CBS mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L;P <0.001) and 15 weeks (23.9±3.0 versus 13.0±2.3 μmol/L;P <0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% (P <0.05) and thrombomodulin anticoagulant activity was decreased by 20% (P <0.05) in CBS mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS mice, and correlations were observed between plasma total homocysteine and SAH in liver (r =0.54;P <0.001) and brain (r =0.67;P <0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.]]></description><subject>Aminoacid disorders</subject><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - metabolism</subject><subject>Aorta - physiopathology</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Chronic Disease</subject><subject>Cystathionine beta-Synthase - deficiency</subject><subject>Cystathionine beta-Synthase - genetics</subject><subject>Disease Models, Animal</subject><subject>Endothelium, Vascular - physiopathology</subject><subject>Errors of metabolism</subject><subject>Folic Acid - blood</subject><subject>Food, Fortified</subject><subject>Heterozygote</subject><subject>Homocysteine - blood</subject><subject>Hyperhomocysteinemia - blood</subject><subject>Hyperhomocysteinemia - physiopathology</subject><subject>In Vitro Techniques</subject><subject>Liver - metabolism</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Methionine - blood</subject><subject>Methylation</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>S-Adenosylhomocysteine - metabolism</subject><subject>S-Adenosylmethionine - metabolism</subject><subject>Thrombomodulin - metabolism</subject><subject>Vasoconstrictor Agents - pharmacology</subject><subject>Vasodilator Agents - pharmacology</subject><subject>Vasomotor System - drug effects</subject><subject>Vasomotor System - physiopathology</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkU1uFDEQhS0EIsPAki3qBWLnUP7psb2MJsOPFMQisG65_aM2uO3Q7knUO-7ATTgIh-AkOPRIsKqqp09PqvcQek7gnJAdeT0MhAA5B0WJhAdoQ1rKMW8FeYg2AKCwYAzO0JNSvgAQzqh6jM4IYUoIKTdoPCSb58HFoGNzuRR_TGYOOTU62eYQ3a3-e2XfXOML61IuSxzymM1SZheSa0Jq9nXX81C5e-HXT3y9pHnQxf3-_uPS-WCCS3PzIRj3FD3yOhb37DS36PObw6f9O3z18e37_cUVNhyoxNJK74zoKTNaGNsTSneKs95LzX39VKhWabMjQnBKjfVCW0tb1cretpJ7xbbo1ep7M-VvR1fmbgzFuBh1cvlYOgEKBEhRQbyCZsqlTM53N1MY9bR0BLr7fLs1327Nt_IvTsbHfnT2H30KtAIvT4AuRkc_6WRC-c-VM1Jb2CK-Ync5zm4qX-Pxzk3d4HSch672BgwIxbRWBjuQgKtCJPsDBe-VIg</recordid><startdate>20010608</startdate><enddate>20010608</enddate><creator>Dayal, Sanjana</creator><creator>Bottiglieri, Teodoro</creator><creator>Arning, Erland</creator><creator>Maeda, Nobuyo</creator><creator>Malinow, M René</creator><creator>Sigmund, Curt D</creator><creator>Heistad, Donald D</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>7X8</scope></search><sort><creationdate>20010608</creationdate><title>Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice</title><author>Dayal, Sanjana ; Bottiglieri, Teodoro ; Arning, Erland ; Maeda, Nobuyo ; Malinow, M René ; Sigmund, Curt D ; Heistad, Donald D ; Faraci, Frank M ; Lentz, Steven R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4028-8d8fec7b23ca7cdb1226943bf8a4f0927959ac6177422cdf7add25958bd584f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Aminoacid disorders</topic><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - metabolism</topic><topic>Aorta - physiopathology</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Chronic Disease</topic><topic>Cystathionine beta-Synthase - deficiency</topic><topic>Cystathionine beta-Synthase - genetics</topic><topic>Disease Models, Animal</topic><topic>Endothelium, Vascular - physiopathology</topic><topic>Errors of metabolism</topic><topic>Folic Acid - blood</topic><topic>Food, Fortified</topic><topic>Heterozygote</topic><topic>Homocysteine - blood</topic><topic>Hyperhomocysteinemia - blood</topic><topic>Hyperhomocysteinemia - physiopathology</topic><topic>In Vitro Techniques</topic><topic>Liver - metabolism</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Methionine - blood</topic><topic>Methylation</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>S-Adenosylhomocysteine - metabolism</topic><topic>S-Adenosylmethionine - metabolism</topic><topic>Thrombomodulin - metabolism</topic><topic>Vasoconstrictor Agents - pharmacology</topic><topic>Vasodilator Agents - pharmacology</topic><topic>Vasomotor System - drug effects</topic><topic>Vasomotor System - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dayal, Sanjana</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Maeda, Nobuyo</creatorcontrib><creatorcontrib>Malinow, M René</creatorcontrib><creatorcontrib>Sigmund, Curt D</creatorcontrib><creatorcontrib>Heistad, Donald D</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>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dayal, Sanjana</au><au>Bottiglieri, Teodoro</au><au>Arning, Erland</au><au>Maeda, Nobuyo</au><au>Malinow, M René</au><au>Sigmund, Curt D</au><au>Heistad, Donald D</au><au>Faraci, Frank M</au><au>Lentz, Steven R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2001-06-08</date><risdate>2001</risdate><volume>88</volume><issue>11</issue><spage>1203</spage><epage>1209</epage><pages>1203-1209</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract><![CDATA[Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS) and wild-type (CBS) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS mice compared with CBS mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L;P <0.001) and 15 weeks (23.9±3.0 versus 13.0±2.3 μmol/L;P <0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% (P <0.05) and thrombomodulin anticoagulant activity was decreased by 20% (P <0.05) in CBS mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS mice, and correlations were observed between plasma total homocysteine and SAH in liver (r =0.54;P <0.001) and brain (r =0.67;P <0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.]]></abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>11397788</pmid><doi>10.1161/hh1101.092180</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation research, 2001-06, Vol.88 (11), p.1203-1209 |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete |
| subjects | Aminoacid disorders Animals Aorta - drug effects Aorta - metabolism Aorta - physiopathology Biological and medical sciences Brain - metabolism Chronic Disease Cystathionine beta-Synthase - deficiency Cystathionine beta-Synthase - genetics Disease Models, Animal Endothelium, Vascular - physiopathology Errors of metabolism Folic Acid - blood Food, Fortified Heterozygote Homocysteine - blood Hyperhomocysteinemia - blood Hyperhomocysteinemia - physiopathology In Vitro Techniques Liver - metabolism Medical sciences Metabolic diseases Methionine - blood Methylation Mice Mice, Inbred C57BL Mice, Knockout S-Adenosylhomocysteine - metabolism S-Adenosylmethionine - metabolism Thrombomodulin - metabolism Vasoconstrictor Agents - pharmacology Vasodilator Agents - pharmacology Vasomotor System - drug effects Vasomotor System - physiopathology |
| title | Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice |
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