{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:08:06Z","timestamp":1791986886030,"version":"4.4.0"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,5]]},"abstract":"\n BACKGROUND:<\/jats:title>\n \n The\n ZC3HC1<\/jats:italic>\n (zinc finger C3HC-type containing 1) gene has been linked to various cardiovascular traits, including coronary artery disease, blood pressure, and carotid intima-media thickness with opposing effects. This study aimed to investigate the role of ZC3HC1 in smooth muscle cell (SMC) biology and its contribution to neointima formation.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n SMC phenotypes (proliferation and migration) were analyzed according to rs11556924 genotype, small interfering RNA\u2013mediated knockdown of human ZC3HC1, or complete knockout of murine Zc3hc1. Transcriptomic profiling and contractile marker expression were used to define SMC states. The impact of complete gene loss on injury-induced neointima formation was examined in vivo using Zc3hc1\n \u2212\/\u2212<\/jats:sup>\n mice. Subcellular localization of murine NIPA (nuclear interaction partner of anaplastic lymphoma kinase; encoded by Zc3hc1) during the cell cycle was analyzed by immunofluorescence microscopy.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n The coronary artery disease\u2013protective rs11556924-T allele was associated with reduced\n ZC3HC1<\/jats:italic>\n expression and enhanced SMC migration.\n ZC3HC1<\/jats:italic>\n knockdown in human SMCs replicated this phenotype, increasing migration and proliferation, and leading to CCNB1 (cyclin B1) accumulation with reduced expression of contractile markers. Following arterial injury,\n Zc3hc1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice exhibited exaggerated neointima formation and enhanced SMC migration. In contrast to small interfering RNA experiments, complete\n Zc3hc1<\/jats:italic>\n loss resulted in reduced SMC proliferation and lower CCNB1 levels. Transient knockdown of\n Zc3hc1<\/jats:italic>\n in wild-type mouse SMCs increased proliferation, recapitulating findings in human cells. Immunofluorescence revealed colocalization of NIPA and CCNB1 at the cleavage furrow, suggesting a role in mitotic exit.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n ZC3HC1 acts as a dosage-sensitive modulator of SMC phenotype. Partial reduction promotes a synthetic, proliferative state and neointima formation, while complete loss induces a quiescent phenotype. These findings provide mechanistic insight into the paradoxical clinical associations of the rs11556924-T allele and identify ZC3HC1 as a potential target for modulating SMC phenotypes in vascular disease.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323659","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:00:14Z","timestamp":1773306014000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Deficiency of\n ZC3HC1<\/i>\n Modulates Vascular Smooth Muscle Cell Phenotype and Increases Neointima Formation"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-9554","authenticated-orcid":true,"given":"Redouane","family":"Aherrahrou","sequence":"first","affiliation":[{"name":"Institute for Cardiogenetics, Universit\u00e4t zu L\u00fcbeck, Germany (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."},{"name":"DZHK Partner Site North (German Centre for Cardiovascular Research) (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."},{"name":"University Heart Centre L\u00fcbeck, Germany (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."},{"name":"Immunology Center of Georgia (R.A.), Medical College of Georgia, Augusta University."},{"name":"Department of Pharmacology and Toxicology (R.A.), Medical College of Georgia, Augusta University."},{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (R.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6237-0803","authenticated-orcid":true,"given":"Tobias","family":"Reinberger","sequence":"additional","affiliation":[{"name":"Institute for Cardiogenetics, Universit\u00e4t zu L\u00fcbeck, Germany (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."},{"name":"DZHK Partner Site North (German Centre for Cardiovascular Research) (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."},{"name":"University Heart Centre L\u00fcbeck, Germany (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-5374","authenticated-orcid":true,"given":"Julia","family":"Werner","sequence":"additional","affiliation":[{"name":"Deutsches Herzzentrum M\u00fcnchen, Technische Universit\u00e4t M\u00fcnchen and DZHK (German Centre for Cardiovascular Research) 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