{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:21:12Z","timestamp":1792095672894,"version":"4.4.0"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      -adenosylhomocysteine (SAH) is a novel risk factor of cardiovascular disease. SAHH (\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      -adenosylhomocysteine hydrolase) inhibition leads to SAH accumulation and promotes the formation and development of atherosclerosis. However, the role and underlying mechanism of SAHH in the stability of advanced atherosclerotic plaque are still unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>ApoE-deficient mice with heterozygous SAHH knockout or vascular smooth muscle cell (VSMC)\u2013specific or macrophage-specific SAHH knockout were used to investigate the effect of SAHH deficiency on atherosclerotic plaque stability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Heterozygote or VSMCs-specific but not macrophage-specific knockout of SAHH induced VSMC phenotype switching and decreased plaque stability. Whole-genome bisulfite sequencing and RNA sequencing showed that hypomethylation and upregulation of KLF4 (Kr\u00fcppel-like factor 4) might be associated with SAHH deletion\u2013induced VSMC phenotype switching. Mechanistically, SAHH deficiency resulted in SAH accumulation and induced KLF4 upregulation by inhibiting DNMT (DNA methyltransferase) 3b and leading to hypomethylation of the KLF4 promoter. Furthermore, SAHH deletion reactivated OCT4 (octamer-binding transcription factor 4)\u2013mediated VSMCs migration in a KLF4-dependent manner via TET (tetmethylcytosine dioxygenase) 1\u2013mediated hydroxymethylation of OCT4 promoter. In addition, SAHH deletion resulted in downregulation of TET2-mediated hydroxymethylation of the KLF4 promoter via inhibition of AMPK (AMP-activated protein kinase). Finally, decreased SAHH activity and elevated SAH levels were associated with unstable atherosclerotic plaque in patients with coronary artery disease or ischemic stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These results suggest that SAHH deficiency decreased the stability of atherosclerotic plaques and induced VSMC phenotype switching via epigenetic upregulation of KLF4 and OCT4.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.324115","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T09:00:43Z","timestamp":1778749243000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["SAHH Deficiency Decreases Stability of Atherosclerotic Plaque and Induces VSMC Phenotype Switching via Epigenetic Upregulation of KLF4 and OCT4"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-9397","authenticated-orcid":true,"given":"Si","family":"Liu","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digestive Cancer Research, Cardiovascular Center, The Seventh Affiliated Hospital (S.L., T.H., M.P., Y.W., X.D., B.L., Y.H., Y.X.), Sun Yat-sen University, Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1502-8529","authenticated-orcid":true,"given":"Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digestive Cancer Research, Cardiovascular Center, The Seventh Affiliated Hospital (S.L., T.H., M.P., Y.W., X.D., B.L., Y.H., Y.X.), Sun Yat-sen University, Shenzhen, Guangdong, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-2465","authenticated-orcid":true,"given":"Xin","family":"Dai","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digestive Cancer Research, Cardiovascular Center, The Seventh Affiliated Hospital (S.L., T.H., M.P., Y.W., X.D., B.L., Y.H., Y.X.), Sun Yat-sen University, Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8322-3290","authenticated-orcid":true,"given":"Chaoqun","family":"Liu","sequence":"additional","affiliation":[{"name":"Jinan University, School of Public Health, Guangzhou, Guangdong, China (C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Huang","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Disease Control and Prevention, Toxicology Research Institute, Guangdong, China 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