{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:13:43Z","timestamp":1789578823761,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2016\/23\/N\/NZ3\/01216"],"award-info":[{"award-number":["2016\/23\/N\/NZ3\/01216"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2018\/29\/B\/NZ4\/00771"],"award-info":[{"award-number":["2018\/29\/B\/NZ4\/00771"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2019\/33\/B\/NZ4\/01760"],"award-info":[{"award-number":["2019\/33\/B\/NZ4\/01760"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2021\/43\/B\/NZ4\/00339"],"award-info":[{"award-number":["2021\/43\/B\/NZ4\/00339"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17GRNT32910002"],"award-info":[{"award-number":["17GRNT32910002"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2024,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR\u201022\u20103p and miR\u20101229\u20103p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy\u2010thiolactone and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Hcy\u2010protein. Here, we examined the effects of these metabolites on miR\u201022\u20103p, miR\u20101229\u20103p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR\u2010, and autophagy\u2010related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Hcy\u2010protein, Hcy\u2010thiolactone, or Hcy upregulated miR\u201022\u20103p and miR\u20101229\u20103p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho\u2010mTOR. Autophagy\u2010related proteins (BECN1, ATG5, ATG7, lipidated LC3\u2010II, and LC3\u2010II\/LC3\u2010I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR\u201022\u20103p, Phf8, mTOR\u2010 and autophagy\u2010related proteins\/mRNAs in\u00a0vivo in hearts of\n                    <jats:italic>Cbs<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR\u201022\u20103p or miR\u20101229\u20103p abrogated the effects of Hcy\u2010thiolactone,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Hcy\u2010protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR\u2010, and autophagy\u2010related proteins\/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR\u201022\u20103p and miR\u20101229\u20103p expression, which then dysregulate the PHF8\/H4K20me1\/mTOR\/autophagy pathway, important for vascular homeostasis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202302116r","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T03:04:16Z","timestamp":1727319856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Homocysteine metabolites impair the\n                    <scp>PHF8<\/scp>\n                    \/\n                    <scp>H4K20me1<\/scp>\n                    \/\n                    <scp>mTOR<\/scp>\n                    \/autophagy pathway by upregulating the expression of histone demethylase\n                    <scp>PHF8<\/scp>\n                    \u2010targeting\n                    <scp>microRNAs<\/scp>\n                    in human vascular endothelial cells and mice"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3908-7735","authenticated-orcid":false,"given":"\u0141ukasz","family":"Witucki","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology Pozna\u0144 University of Life Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-4409","authenticated-orcid":false,"given":"Hieronim","family":"Jakubowski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology Pozna\u0144 University of Life Sciences  Pozna\u0144 Poland"},{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, International Center for Public Health Rutgers University  Newark New Jersey 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