{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:57:57Z","timestamp":1781881077526,"version":"3.54.5"},"reference-count":117,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"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":["Circulation"],"published-print":{"date-parts":[[2026,5,26]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet\u2013fed Apoe (apolipoprotein E)\u2013deficient (\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) mice with\n                      <jats:italic toggle=\"yes\">Prmt3<\/jats:italic>\n                      haploinsufficiency were used to examine the role of PRMT3 in aortic valve calcification. The effects of PRMT3 inhibition (SGC707) and degradation (PROTAC compound 11) on aortic valve calcification were investigated in vivo. To elucidate the mechanisms underlying the procalcific effects of PRMT3, we performed immunoprecipitation coupled with liquid chromatography\u2013tandem mass spectrometry and coimmunoprecipitation assays with an enzymatically inactive PRMT3 variant as well as arginine-to-lysine and lysine-to-alanine substitution PCSK9 variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover,\n                      <jats:italic toggle=\"yes\">Prmt3<\/jats:italic>\n                      haploinsufficiency markedly ameliorated aortic valve calcification in high-cholesterol diet\u2013fed\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, as revealed by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic measures (decreased peak transvalvular jet velocity, reduced mean transvalvular pressure gradient, and increased aortic valve area), and decreased levels of osteogenic markers OPN (osteopontin) and Osx (Osterix) in the aortic valve leaflets. In addition, anticalcific effects were achieved through pharmacologic PRMT3 inhibition with SGC707 and PRMT3 degradation through PROTAC. Consistent with the in vivo results, we found that PRMT3 promoted the osteogenic differentiation of human valvular interstitial cells through its enzymatic activity. Mechanistically, we revealed that PRMT3 catalyzed the asymmetric dimethylation of PCSK9 at the arginine 582 residue (R582), which was accompanied by a prolonged PCSK9 half-life. This methylation prevented the binding of the E3 ligase CHIP (carboxyl terminus of Hsc70-interacting protein) to PCSK9 at lysine 575 (K575), thereby abrogating ubiquitination-mediated degradation of PCSK9, which is a procalcific factor, and accelerating aortic valve calcification progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid\u2013osteogenic coupling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.078830","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:00:45Z","timestamp":1773050445000},"page":"1637-1660","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["PRMT3-Mediated Arginine Methylation Stabilizes PCSK9 to Promote Aortic Valve Calcification"],"prefix":"10.1161","volume":"153","author":[{"given":"Xi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery (X.Z., Y.H., X.S., W.Y., S.W., X.L., R.L., K.Z., Y. Liu, Z.Z., Z.T., Y. Li, Y.W., J.X., J.W.), Wuhan, China"},{"name":"Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and Key Laboratory of Biological Targeted Therapy, Ministry of Education (X.Z., J.X., J.W.), Wuhan, China"},{"name":"Hubei Key Laboratory of Biological Targeted Therapy, Wuhan, China (X.Z., J.X., J.W.)."},{"name":"Key Laboratory of Organ Transplantation, Ministry of Education and NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China (X.Z., J.X., J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanglin","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (X.Z., Y.H., X.S., W.Y., S.W., X.L., R.L., K.Z., Y. Liu, Z.Z., Z.T., Y. Li, Y.W., J.X., J.W.), Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Han","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China (D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (X.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (X.Z., Y.H., X.S., W.Y., S.W., X.L., R.L., K.Z., Y. Liu, Z.Z., Z.T., Y. Li, Y.W., J.X., J.W.), Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine (L.Z.), Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Pain (Z.G.), Wuhan, China"},{"name":"Institute of Anesthesia and Critical Care Medicine (Z.G.), Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2044-6734","authenticated-orcid":true,"given":"Weicong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (X.Z., Y.H., X.S., W.Y., S.W., X.L., R.L., K.Z., Y. Liu, Z.Z., Z.T., Y. 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