{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T20:38:29Z","timestamp":1794083909824,"version":"4.8.0"},"reference-count":191,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,17]],"date-time":"2019-02-17T00:00:00Z","timestamp":1550361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.<\/jats:p>","DOI":"10.3390\/ijms20040867","type":"journal-article","created":{"date-parts":[[2019,2,17]],"date-time":"2019-02-17T22:11:50Z","timestamp":1550441510000},"page":"867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":316,"title":["The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8381-0628","authenticated-orcid":false,"given":"Ruben","family":"Esse","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-890X","authenticated-orcid":false,"given":"Madalena","family":"Barroso","sequence":"additional","affiliation":[{"name":"University Children\u2019s Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Tavares de Almeida","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Genetics, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-0741","authenticated-orcid":false,"given":"Rita","family":"Castro","sequence":"additional","affiliation":[{"name":"Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal"},{"name":"Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal"},{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,17]]},"reference":[{"key":"ref_1","unstructured":"(2018, October 20). 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