{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:43:20Z","timestamp":1784879000941,"version":"3.55.0"},"reference-count":46,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,7,12]],"date-time":"2013-07-12T00:00:00Z","timestamp":1373587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Homocysteine is an intermediate product formed during the metabolism of methionine, and is increased in cells with folate deficiency. Patients with hyperhomocysteinemia tend to develop cardiovascular disease. Here, we have examined the molecular mechanisms underlying the anti\u2010proliferative and anti\u2010migratory effects of folate on homocysteine\u2010challenged rat aortic smooth muscle cells (<jats:styled-content style=\"fixed-case\">RASMC<\/jats:styled-content>s).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cultures of RASMC were challenged with homocysteine and then incubated with folate added. Changes in p21\/p27, <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content> were followed by RT\u2010PCR, Western blotting and immunocytochemistry. Transfection and anti\u2010sense techniques were also used. Cell viability, growth and migration were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Folate up\u2010regulated p21\/p27 through a Src\/<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\u2010dependent mechanism that accounted for its anti\u2010proliferative effects on <jats:styled-content style=\"fixed-case\">RASMC<\/jats:styled-content>. Folate protected <jats:styled-content style=\"fixed-case\">RASMC<\/jats:styled-content> from the effects of homocysteine by reducing <jats:styled-content style=\"fixed-case\">AKT1<\/jats:styled-content>, focal adhesion kinase (<jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>), paxillin, and <jats:styled-content style=\"fixed-case\">p190RhoGAP<\/jats:styled-content> activation\/phosphorylation, along with cytosolic levels of p21 and p27, and increasing <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content> activation. Overexpression of <jats:styled-content style=\"fixed-case\">AKT1<\/jats:styled-content>, but not of <jats:styled-content style=\"fixed-case\">AKT2<\/jats:styled-content>, induced p21\/p27 phosphorylation and increased cytosolic p21\/p27 levels, as did homocysteine treatment. By contrast, and similarly to folate treatment, transfection with dominant negative (<jats:styled-content style=\"fixed-case\">DN) AKT1<\/jats:styled-content> counteracted these effects. Additionally, <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> was shown to be an upstream target of <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content> activation. In <jats:styled-content style=\"fixed-case\">RASMC<\/jats:styled-content> overexpressing constitutively active <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content>, activation of <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content> mediated the anti\u2010migratory effects of folate. Addition of <jats:styled-content style=\"fixed-case\">Y27632<\/jats:styled-content> (a <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content> inhibitor) and <jats:styled-content style=\"fixed-case\">DNRhoA<\/jats:styled-content> counteracted the anti\u2010migratory effects, confirming <jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content> involvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications<\/jats:title><jats:p>Folate was anti\u2010proliferative and anti\u2010migratory in homocysteine\u2010challenged <jats:styled-content style=\"fixed-case\">RASMC.<\/jats:styled-content> Mechanisms underlying folate\u2010mediated protection against the proatherosclerotic effects of homocysteine have been delineated.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12130","type":"journal-article","created":{"date-parts":[[2013,2,20]],"date-time":"2013-02-20T12:57:57Z","timestamp":1361365077000},"page":"1447-1460","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular mechanisms underlying the anti\u2010proliferative and anti\u2010migratory effects of folate on homocysteine\u2010challenged rat aortic smooth muscle cells"],"prefix":"10.1111","volume":"169","author":[{"given":"Ying","family":"Chou","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences Taipei Medical University  Taipei Taiwan"},{"name":"Department of Physiology School of Medicine Taipei Medical University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Chen","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences Taipei Medical University  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