{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:54:53Z","timestamp":1790848493519,"version":"4.1.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>FTO (fat mass and obesity-associated) protein, a key N6-methyladenosine demethylase, plays a critical role in cardiovascular disease. However, its function in vascular calcification remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      High phosphate (Pi) was used to induce calcification in vascular smooth muscle cells (VSMCs) and aortic rings, and high-dose vitamin D\n                      <jats:sub>3<\/jats:sub>\n                      (vD\n                      <jats:sub>3<\/jats:sub>\n                      ) was used to induce vascular calcification in mice. FTO expression was modulated using adenovirus, adeno-associated virus, and siRNA. To identify FTO targets, we performed integrated MeRIP sequencing and RNA sequencing analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      FTO expression was significantly downregulated in calcified VSMCs, mouse arteries, and human arteries relative to their noncalcified counterparts. Silencing of\n                      <jats:italic toggle=\"yes\">Fto<\/jats:italic>\n                      increased high Pi\u2013induced osteogenic gene expression and calcification in VSMCs. Conversely, overexpression of\n                      <jats:italic toggle=\"yes\">Fto<\/jats:italic>\n                      resulted in the opposite effect. These results were confirmed in high Pi\u2013induced rat aortic ring calcification and a vD\n                      <jats:sub>3<\/jats:sub>\n                      -induced mouse model of vascular calcification through treatment with the FTO inhibitor F,B-2,3. Intriguingly, the ALP (alkaline phosphatase) inhibitor TNAP-IN-1 or levamisole hydrochloride partially reduced FTO inhibition-induced increases in VSMC calcification, rat aortic ring calcification, and vascular calcification in mice. Adeno-associated virus\u2013mediated VSMC-specific overexpression of\n                      <jats:italic toggle=\"yes\">Fto<\/jats:italic>\n                      significantly attenuated vascular calcification in mice with overloaded vD\n                      <jats:sub>3<\/jats:sub>\n                      . Integrated MeRIP sequencing and RNA sequencing identified that\n                      <jats:italic toggle=\"yes\">Pcsk9<\/jats:italic>\n                      is a potential target of FTO. Knockdown of FTO increased N6-methyladenosine methylation and mRNA stability of\n                      <jats:italic toggle=\"yes\">Pcsk9<\/jats:italic>\n                      , and its secretion by VSMCs. In addition, knockdown of\n                      <jats:italic toggle=\"yes\">Fto<\/jats:italic>\n                      enhanced the activation of NF-\u03baB (nuclear factor-\u03baB) signaling and increased the expression of inflammatory cytokines, including\n                      <jats:italic toggle=\"yes\">IL-6<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Icam1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Vcam1<\/jats:italic>\n                      , which were attenuated by concomitant knockdown of\n                      <jats:italic toggle=\"yes\">Pcsk9<\/jats:italic>\n                      . Finally, knockdown of\n                      <jats:italic toggle=\"yes\">Pcsk9<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">p65<\/jats:italic>\n                      abolished silencing of the\n                      <jats:italic toggle=\"yes\">Fto<\/jats:italic>\n                      -induced increase in osteogenic transition and calcification in VSMCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our results suggest that FTO may inhibit vascular calcification at least in part through\n                      <jats:italic toggle=\"yes\">Pcsk9<\/jats:italic>\n                      -mediated modulation of NF-\u03baB signaling and altered ALP activity. FTO may therefore be an attractive target for the treatment of vascular calcification.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324532","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:00:18Z","timestamp":1790845218000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["M\n                    <sup>6<\/sup>\n                    A Demethylase FTO Targets Pcsk9 to Inhibit Vascular Calcification in Chronic Kidney Disease"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0891-9288","authenticated-orcid":true,"given":"Yuchen","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, GMU-GIBH Joint School of Life Sciences, The Second Affiliated Hospital, Guangzhou Medical 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Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, China (Y.X., H.Z., G.Z., Liang Yuan, K.L., D.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2204-8323","authenticated-orcid":true,"given":"Liang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, China (Y.X., H.Z., G.Z., Liang Yuan, K.L., D.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8261-0211","authenticated-orcid":true,"given":"Kun","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cardiovascular Disease, Guangdong Key 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