{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T14:33:39Z","timestamp":1778078019685,"version":"3.51.4"},"reference-count":34,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,1,1]]},"abstract":"<jats:p>Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine\/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1\/2 activity but neither ERK1\/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in\u00a0vitro and in\u00a0vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1\/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.<\/jats:p>","DOI":"10.1042\/cs20160664","type":"journal-article","created":{"date-parts":[[2016,10,5]],"date-time":"2016-10-05T02:39:32Z","timestamp":1475635172000},"page":"141-154","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload"],"prefix":"10.1042","volume":"131","author":[{"given":"Wei-ming","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-fan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-fu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-hui","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-yun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-chun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-wei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2016,12,23]]},"reference":[{"key":"2021113010524081400_B1","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1093\/eurheartj\/ehv548","article-title":"Heart failure: when form fails to follow function","volume":"37","author":"Katz","year":"2015","journal-title":"Eur. Heart J."},{"key":"2021113010524081400_B2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrcardio.2010.165","article-title":"Epidemiology and risk profile of heart failure","volume":"8","author":"Bui","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"2021113010524081400_B3","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1161\/CIR.0000000000000152","article-title":"Heart disease and stroke statistics\u20132015 update: a report from the American Heart Association","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"2021113010524081400_B4","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/nrm1983","article-title":"Regulation of cardiac hypertrophy by intracellular signalling pathways","volume":"7","author":"Heineke","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021113010524081400_B5","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1007\/s00204-015-1477-x","article-title":"Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets","volume":"89","author":"Tham","year":"2015","journal-title":"Arch. Toxicol."},{"key":"2021113010524081400_B6","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1042\/BJ20082234","article-title":"Dual-specificity phosphatases: critical regulators with diverse cellular targets","volume":"418","author":"Patterson","year":"2009","journal-title":"Biochem. J."},{"key":"2021113010524081400_B7","doi-asserted-by":"publisher","first-page":"H801","DOI":"10.1152\/ajpheart.00908.2011","article-title":"Angiotensin-(1-7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1","volume":"302","author":"McCollum","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113010524081400_B8","doi-asserted-by":"publisher","first-page":"35786","DOI":"10.1074\/jbc.M102479200","article-title":"The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival","volume":"276","author":"Schwartzbauer","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B9","doi-asserted-by":"publisher","first-page":"23991","DOI":"10.1074\/jbc.274.34.23991","article-title":"Identification of the human YVH1 protein-tyrosine phosphatase orthologue reveals a novel zinc binding domain essential for in\u00a0vivo function","volume":"274","author":"Muda","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B10","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/ncb1258","article-title":"Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance","volume":"7","author":"MacKeigan","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"2021113010524081400_B11","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1042\/BJ20081484","article-title":"The dual-specificity phosphatase hYVH1 interacts with Hsp70 and prevents heat-shock-induced cell death","volume":"418","author":"Sharda","year":"2009","journal-title":"Biochem. J."},{"key":"2021113010524081400_B12","doi-asserted-by":"publisher","first-page":"22853","DOI":"10.1074\/jbc.M109.038612","article-title":"Redox regulation of the human dual specificity phosphatase YVH1 through disulfide bond formation","volume":"284","author":"Bonham","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.fgb.2015.02.011","article-title":"Identification of putative negative regulators of yeast signaling through a screening for protein phosphatases acting on cell wall integrity and mating MAPK pathways","volume":"77","author":"Sacrist\u00e1n-Reviriego","year":"2015","journal-title":"Fungal Genet. Biol."},{"key":"2021113010524081400_B14","doi-asserted-by":"publisher","first-page":"11267","DOI":"10.1038\/ncomms11267","article-title":"The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling","volume":"7","author":"Ji","year":"2016","journal-title":"Nat. Commun."},{"key":"2021113010524081400_B15","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1161\/HYPERTENSIONAHA.115.05469","article-title":"Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy novelty and significance","volume":"66","author":"Jiang","year":"2015","journal-title":"Hypertension"},{"key":"2021113010524081400_B16","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1038\/ncomms4303","article-title":"IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling","volume":"5","author":"Jiang","year":"2014","journal-title":"Nat. Commun."},{"key":"2021113010524081400_B17","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1161\/CIRCULATIONAHA.110.970673","article-title":"Mitogen-activated protein kinase inhibitors improve heart function and prevent fibrosis in cardiomyopathy caused by mutation in lamin A\/C gene","volume":"123","author":"Wu","year":"2011","journal-title":"Circulation"},{"key":"2021113010524081400_B18","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1161\/CIRCULATIONAHA.106.679589","article-title":"Mitogen-activated protein kinases in heart development and diseases","volume":"116","author":"Wang","year":"2007","journal-title":"Circulation"},{"key":"2021113010524081400_B19","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1152\/physrev.00054.2009","article-title":"Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale","volume":"90","author":"Rose","year":"2010","journal-title":"Physiol. Rev."},{"key":"2021113010524081400_B20","doi-asserted-by":"publisher","first-page":"32406","DOI":"10.1074\/jbc.M000841200","article-title":"A novel cytosolic dual specificity phosphatase, interacting with glucokinase, increases glucose phosphorylation rate","volume":"275","author":"Munoz-Alonso","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B21","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1042\/BJ20071512","article-title":"Negative-feedback regulation of FGF signalling by DUSP6\/MKP-3 is driven by ERK1\/2 and mediated by Ets factor binding to a conserved site within the DUSP6\/MKP-3 gene promoter","volume":"412","author":"Ekerot","year":"2008","journal-title":"Biochem. J."},{"key":"2021113010524081400_B22","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1074\/jbc.272.2.1368","article-title":"The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42\/p44MAPK cascade","volume":"272","author":"Brondello","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B23","doi-asserted-by":"publisher","first-page":"9806","DOI":"10.1073\/pnas.1301509110","article-title":"Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy","volume":"110","author":"Ferguson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010524081400_B24","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1161\/01.RES.88.1.88","article-title":"The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in\u00a0vitro and in\u00a0vivo","volume":"88","author":"Bueno","year":"2001","journal-title":"Circ. Res."},{"key":"2021113010524081400_B25","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1161\/CIRCRESAHA.112.272963","article-title":"Unrestrained p38 MAPK activation in Dusp1\/4 double-null mice induces cardiomyopathy","volume":"112","author":"Auger-Messier","year":"2013","journal-title":"Circ. Res."},{"key":"2021113010524081400_B26","doi-asserted-by":"publisher","first-page":"14074","DOI":"10.1073\/pnas.0610906104","article-title":"Genetic inhibition of cardiac ERK1\/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in\u00a0vivo","volume":"104","author":"Purcell","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010524081400_B27","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1161\/CIRCRESAHA.108.193318","article-title":"The I B kinase \/nuclear factor B signaling pathway protects the heart from hemodynamic stress mediated by the regulation of manganese superoxide dismutase expression","volume":"105","author":"Hikoso","year":"2009","journal-title":"Circ. Res."},{"key":"2021113010524081400_B28","doi-asserted-by":"publisher","first-page":"5079","DOI":"10.1093\/emboj\/cdg474","article-title":"c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling","volume":"22","author":"Liang","year":"2003","journal-title":"EMBO J."},{"key":"2021113010524081400_B29","doi-asserted-by":"publisher","first-page":"5423","DOI":"10.1074\/jbc.273.10.5423","article-title":"Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells","volume":"273","author":"Wang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B30","doi-asserted-by":"publisher","first-page":"5079","DOI":"10.1093\/emboj\/cdg474","article-title":"c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling","volume":"22","author":"Liang","year":"2003","journal-title":"EMBO J."},{"key":"2021113010524081400_B31","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1161\/CIRCRESAHA.108.188292","article-title":"Cardiac-specific deletion of Mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth","volume":"104","author":"Liu","year":"2009","journal-title":"Circ. Res."},{"key":"2021113010524081400_B32","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.yjmcc.2011.01.013","article-title":"Deprivation of MKK7\u00a0in cardiomyocytes provokes heart failure in mice when exposed to pressure overload","volume":"50","author":"Liu","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021113010524081400_B33","doi-asserted-by":"publisher","first-page":"15330","DOI":"10.1074\/jbc.M314142200","article-title":"Targeted activation of c-Jun N-terminal kinase in\u00a0vivo induces restrictive cardiomyopathy and conduction defects","volume":"279","author":"Petrich","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021113010524081400_B34","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1096\/fj.02-0438fje","article-title":"Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre-loxP-mediated DNA recombination","volume":"17","author":"Petrich","year":"2003","journal-title":"FASEB J."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/2\/141\/445219\/cs1310141.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/2\/141\/445219\/cs1310141.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T11:43:10Z","timestamp":1638272590000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/131\/2\/141\/71648\/Dual-specific-phosphatase-12-ameliorates-cardiac"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,23]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2017,1,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20160664","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,23]]}}}