{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T09:43:27Z","timestamp":1784972607319,"version":"3.55.0"},"reference-count":30,"publisher":"Portland Press Ltd.","issue":"10","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,5,31]]},"abstract":"<jats:p>Cardiac hypertrophy (CH) is a major independent risk factor for heart failure and mortality. However, therapeutic interventions that target hypertrophy signaling in a load-independent way are unavailable. In a recent issue of Clinical Science (vol. 132, issue 6, 685-699), Ma et al. describe that the anti-inflammatory drug leflunomide markedly antagonized CH, dysfunction, and fibrosis induced by aortic banding or angiotensin-II in mice or by agonists in cultured cells. Unexpectedly, this occurred not via anti-inflammatory mechanisms but rather via inhibtion of Akt (protein kinase B, PKB) signaling. We further discuss the mechanisms underlying Akt activation and its effects on CH and review possible mechanisms of leflunomide effects. Despite some caveats, the availability of such a newly repurposed compound to treat CH can be a relevant advance.<\/jats:p>","DOI":"10.1042\/cs20180228","type":"journal-article","created":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T15:40:13Z","timestamp":1527262813000},"page":"1069-1073","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Leflunomide counter<u>\n                     <i>akt<\/i>\n                  <\/u>s cardiac hypertrophy"],"prefix":"10.1042","volume":"132","author":[{"given":"Luciana\u00a0A.","family":"Pescatore","sequence":"first","affiliation":[{"name":"Vascular Biology Laboratory, Heart Institute (InCor), University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco R.M.","family":"Laurindo","sequence":"additional","affiliation":[{"name":"Vascular Biology Laboratory, Heart Institute (InCor), University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,5,25]]},"reference":[{"key":"2021113011065056400_B1","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1016\/j.jacc.2013.11.053","article-title":"The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021113011065056400_B2","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1172\/JCI24178","article-title":"Protein kinase cascades in the regulation of cardiac hypertrophy","volume":"115","author":"Dorn","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021113011065056400_B3","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1161\/HYPERTENSIONAHA.109.136655","article-title":"Regression of left ventricular mass by antihypertensive treatment: a meta-analysis of randomized comparative studies","volume":"54","author":"Fagard","year":"2009","journal-title":"Hypertension"},{"key":"2021113011065056400_B4","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1093\/eurheartj\/ehv633","article-title":"Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial","volume":"37","author":"Mancia","year":"2016","journal-title":"Eur. Heart J."},{"key":"2021113011065056400_B5","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1042\/CS20180160","article-title":"A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice","volume":"132","author":"Ma","year":"2018","journal-title":"Clin. Sci. (Lond.)"},{"key":"2021113011065056400_B6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12967-017-1131-x","article-title":"The active metabolite of leflunomide, A77 1726, attenuates inflammatory arthritis in mice with spontaneous arthritis via induction of heme oxygenase-1","volume":"15","author":"Moon","year":"2017","journal-title":"J. Transl. Med."},{"key":"2021113011065056400_B7","doi-asserted-by":"publisher","first-page":"12398","DOI":"10.1074\/jbc.270.21.12398","article-title":"Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide","volume":"270","author":"Xu","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021113011065056400_B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semcancer.2017.05.011","article-title":"AGC kinases, mechanisms of regulation and innovative drug development","volume":"48","author":"Leroux","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"2021113011065056400_B9","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.vph.2015.05.008","article-title":"The critical role of Akt in cardiovascular function","volume":"74","author":"Abeyrathna","year":"2015","journal-title":"Vascul. Pharmacol."},{"key":"2021113011065056400_B10","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1161\/ATVBAHA.118.310748","article-title":"Endothelial cell autonomous role of Akt1: regulation of vascular tone and ischemia-induced arteriogenesis","volume":"38","author":"Lee","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113011065056400_B11","doi-asserted-by":"publisher","first-page":"12333","DOI":"10.1073\/pnas.172376399","article-title":"Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice","volume":"99","author":"Condorelli","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113011065056400_B12","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1172\/JCI24682","article-title":"Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure","volume":"115","author":"Shiojima","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021113011065056400_B13","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1161\/CIRCULATIONAHA.105.595231","article-title":"Akt1 is required for physiological cardiac growth","volume":"113","author":"DeBosch","year":"2006","journal-title":"Circulation"},{"key":"2021113011065056400_B14","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1161\/CIRCULATIONAHA.114.011079","article-title":"NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt\/mTOR and NFkappaB signaling pathways","volume":"131","author":"Zhao","year":"2015","journal-title":"Circulation"},{"key":"2021113011065056400_B15","doi-asserted-by":"publisher","first-page":"40813","DOI":"10.1074\/jbc.M509255200","article-title":"Regulation of NAD(P)H oxidase by associated protein disulfide isomerase in vascular smooth muscle cells","volume":"280","author":"Janiszewski","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021113011065056400_B16","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/1476-4598-12-133","article-title":"Combining radiotherapy with MEK1\/2, STAT5 or STAT6 inhibition reduces survival of head and neck cancer lines","volume":"12","author":"Stegeman","year":"2013","journal-title":"Mol. Cancer"},{"key":"2021113011065056400_B17","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.neo.2014.08.006","article-title":"Inhibition of p70 S6 kinase (S6K1) activity by A77 1726 and its effect on cell proliferation and cell cycle progress","volume":"16","author":"Doscas","year":"2014","journal-title":"Neoplasia"},{"key":"2021113011065056400_B18","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1097\/TP.0b013e3182007be2","article-title":"Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection","volume":"90","author":"Liacini","year":"2010","journal-title":"Transplantation"},{"key":"2021113011065056400_B19","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1158\/1535-7163.MCT-08-0664","article-title":"Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells","volume":"8","author":"Baumann","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"2021113011065056400_B20","doi-asserted-by":"publisher","first-page":"6479","DOI":"10.4049\/jimmunol.179.10.6479","article-title":"Leflunomide inhibits PDK1\/Akt pathway and induces apoptosis of human mast cells","volume":"179","author":"Sawamukai","year":"2007","journal-title":"J. Immunol."},{"key":"2021113011065056400_B21","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1136\/ard.59.11.841","article-title":"Leflunomide: mode of action in the treatment of rheumatoid arthritis","volume":"59","author":"Breedveld","year":"2000","journal-title":"Ann. Rheum. Dis."},{"key":"2021113011065056400_B22","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.tox.2018.02.003","article-title":"Mitochondrial dysfunction induced by leflunomide and its active metabolite","volume":"396-397","author":"Xuan","year":"2018","journal-title":"Toxicology"},{"key":"2021113011065056400_B23","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1002\/stem.1476","article-title":"Mechanically activated Fyn utilizes mTORC2 to regulate RhoA and adipogenesis in mesenchymal stem cells","volume":"31","author":"Thompson","year":"2013","journal-title":"Stem Cells"},{"key":"2021113011065056400_B24","doi-asserted-by":"publisher","first-page":"4091","DOI":"10.1038\/onc.2015.471","article-title":"Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis","volume":"35","author":"Kim","year":"2016","journal-title":"Oncogene"},{"key":"2021113011065056400_B25","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1016\/j.chembiol.2012.07.017","article-title":"Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site","volume":"19","author":"Busschots","year":"2012","journal-title":"Chem. Biol."},{"key":"2021113011065056400_B26","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1530\/JOE-17-0536","article-title":"Control of hyperglycemia in male mice by leflunomide: mechanisms of action","volume":"237","author":"Chen","year":"2018","journal-title":"J. Endocrinol."},{"key":"2021113011065056400_B27","doi-asserted-by":"publisher","first-page":"e6703","DOI":"10.1371\/journal.pone.0006703","article-title":"Multiparameter phospho-flow analysis of lymphocytes in early rheumatoid arthritis: implications for diagnosis and monitoring drug therapy","volume":"4","author":"Galligan","year":"2009","journal-title":"PLoS ONE"},{"key":"2021113011065056400_B28","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.clim.2015.01.006","article-title":"A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells","volume":"157","author":"Qiao","year":"2015","journal-title":"Clin. Immunol."},{"key":"2021113011065056400_B29","doi-asserted-by":"crossref","first-page":"50401","DOI":"10.18632\/oncotarget.10409","article-title":"Inhibition of canonical WNT\/beta-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells","volume":"7","author":"Chen","year":"2016","journal-title":"Oncotarget"},{"key":"2021113011065056400_B30","volume-title":"Cellular Signal Processing: an Introduction to the Molecular Mechanims of Signal Transduction","author":"Marks","year":"2009","edition":"1st"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/10\/1069\/449054\/cs-2018-0228c.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/10\/1069\/449054\/cs-2018-0228c.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:03:58Z","timestamp":1638273838000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/132\/10\/1069\/77769\/Leflunomide-counterakts-cardiac-hypertrophy"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,25]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,5,31]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20180228","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,25]]}}}