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However, it is not known whether the proatherogenic effect of HHcy in apoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is independent of hyperlipidemia and\/or deficiency of apoE. In this study, a comprehensive dietary approach using C57BL\/6J mice was used to investigate whether HHcy is an independent risk factor for accelerated atherosclerosis or dependent on additional dietary factors that increase plasma lipids and\/or inflam mation. C57BL\/6J mice at 4 wk of age were divided into 6 dietary groups: chow diet (C), chow diet + methionine (C+M), western\u2010type diet (W), western\u2010type diet + methionine (W+M), atherogenic diet (A), or atherogenic diet + methionine (A+M). After 2, 10, 20, or 40 wk on the diets, mice were sacrificed, and the levels of total plasma homocysteine, cysteine, and glutathione, as well as total plasma cholesterol and triglycerides were analyzed. Aortic root sections were examined for atherosclerotic lesions. HHcy was induced in all groups supplemented with methionine, compared to diet\u2010matched control groups. Plasma total cholesterol was significantly increased in mice fed the W or A diet. However, the W diet increased LDL\/IDL and HDL levels, while the A diet significantly elevated plasma VLDL and LDL\/IDL levels without increasing HDL. No differences in plasma total cholesterol levels or lipid profiles were observed between methionine\u2010supplemented groups and the diet\u2010matched control groups. Early atherosclerotic lesions containing macrophage foam cells were only observed in mice fed the A or A + M diet. Furthermore, lesion size was significantly larger in the A + M group compared to the A group at 10 and 20 wk; however, mature lesions were never observed even after 40 wk on these diets. The presence of lymphocytes, increased hyaluronan staining, and the expression of endoplasmic reticulum (ER) stress markers were also increased in atherosclerotic lesions from the A + M group. Taken together, these results suggest that HHcy does not independently cause atherosclerosis in C57BL\/6J mice even in the presence of increased total plasma lipids induced by the W diet. However, HHcy can accelerate atherosclerotic lesion development under dietary conditions that increase plasma VLDL levels and\/or inflammation.\u2014Zhou, J., Werstuck, G. H., Lhot\u00e1k, \u0160., Shi, Y. Y., Tedesco, V., Trigatti, B., Dickhout, J., Majors, A. K., DiBello, P. M., Jacobsen, D. W., Austin, R. C. Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL\/6J mice.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    22, 2569\u20132578 (2008)\n                  <\/jats:p>","DOI":"10.1096\/fj.07-105353","type":"journal-article","created":{"date-parts":[[2008,3,25]],"date-time":"2008-03-25T20:33:50Z","timestamp":1206477230000},"page":"2569-2578","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL\/6J mice"],"prefix":"10.1096","volume":"22","author":[{"given":"Ji","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoff H.","family":"Werstuck","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Department of Biochemistry and Biomedical Sciences McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u0161\u00e1rka","family":"Lhotak","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan Y.","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivienne","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernardo","family":"Trigatti","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Dickhout","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alana K.","family":"Majors","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia M.","family":"DiBello","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Lerner Research Institute Cleveland Clinic Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald W.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Lerner Research Institute Cleveland Clinic Cleveland Ohio USA"},{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard C.","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Henderson Research Centre Hamilton Ontario Canada"},{"name":"Division of Nephrology St. Joseph's Hospital Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,3,25]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1995.03530130055028"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-131-5-199909070-00008"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/hq0901.096582"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10588"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(03)00138-2"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-08-2606"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(95)05740-4"},{"key":"e_1_2_5_9_1","first-page":"167","article-title":"Arterisclerosis due to homocyst(e)inemia. 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