{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T03:43:36Z","timestamp":1773805416897,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011568","name":"Huck Institutes of the Life Sciences","doi-asserted-by":"publisher","award":["09-079-88"],"award-info":[{"award-number":["09-079-88"]}],"id":[{"id":"10.13039\/100011568","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (ApoE \u2212\/\u2212) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation.<\/jats:p>","DOI":"10.3390\/nu12082182","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T10:14:06Z","timestamp":1595499246000},"page":"2182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation"],"prefix":"10.3390","volume":"12","author":[{"given":"Courtney A.","family":"Whalen","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7121-0206","authenticated-orcid":false,"given":"Floyd J.","family":"Mattie","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0664-5411","authenticated-orcid":false,"given":"Cristina","family":"Florindo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"van Zelst","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Medical Center Rotterdam, Erasmus MC University, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2849-7018","authenticated-orcid":false,"given":"Neil K.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"},{"name":"Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Tavares de Almeida","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra G.","family":"Heil","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Medical Center Rotterdam, Erasmus MC University, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Neuberger","sequence":"additional","affiliation":[{"name":"Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA"},{"name":"Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-9570","authenticated-orcid":false,"given":"A. Catharine","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-0741","authenticated-orcid":false,"given":"Rita","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"},{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Research Institute for Medicines (iMed. ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s12012-009-9042-6","article-title":"Quo vadis: Whither homocysteine research?","volume":"9","author":"Joseph","year":"2009","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Esse, R., Barroso, M., de Almeida, I.T., and Castro, R. (2019). The contribution of homocysteine metabolism disruption to endothelial dysfunction: State-of-the-art. Int. J. Mol. 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