{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:53:11Z","timestamp":1790790791399,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence indicates that restraining hypertrophy could be beneficial; here, we discovered that FTY-720, an immunomodulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy\/fibrosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Male C57\/Bl6 mice underwent transverse aortic constriction (TAC) for 1 week followed by FTY-720 treatment for 2 weeks under continuing TAC. Compared with vehicle-treated TAC hearts, FTY-720 significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance. Mechanistic studies led us to discover that FTY-720 appreciably inhibited nuclear factor of activated T-cells (NFAT) activity. Moreover, we found that in primary cardiomyocytes (rat and human) pertussis toxin (G\n              <jats:sub>i<\/jats:sub>\n              -coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720. This observation was confirmed in a mouse model of pressure overload. Interestingly, gene array analysis of TAC hearts revealed that FTY-720 profoundly decreased gene expression of a group of matricellular proteins, of which periostin was prominent. Analysis of periostin protein expression in TAC-myocardium, as well as in rat and human cardiac fibroblasts, confirmed the array data. Moreover, we found that FTY-720 treatment or knockdown of periostin protein was able to inhibit transforming growth factor-\u03b2 responsiveness and decrease collagen expression.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>FTY-720 alleviates existing cardiac hypertrophy\/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu. Together, FTY-720 or its analogues could be a promising new approach for treating hypertrophic\/fibrotic heart disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.112.000123","type":"journal-article","created":{"date-parts":[[2013,6,11]],"date-time":"2013-06-11T02:44:38Z","timestamp":1370918678000},"page":"833-844","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["A Novel Immunomodulator, FTY-720 Reverses Existing Cardiac Hypertrophy and Fibrosis From Pressure Overload by Targeting NFAT (Nuclear Factor of Activated T-cells) Signaling and Periostin"],"prefix":"10.1161","volume":"6","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zi","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoyee","family":"Tsui","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjoy K.","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Zeef","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Jun","family":"Meng","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Travis","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhpal","family":"Prehar","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Berry","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A.","family":"Hanley","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig","family":"Neyses","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Ping","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delvac","family":"Oceandy","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Ke","sequence":"additional","affiliation":[{"name":"From the Faculty of Life Sciences (W.L., H.T., S.K.C., L.Z., Q.-J.M., M.T., X.W.), Faculty of Medical and Human Sciences (M.Z., H.T., S.P., A.B., N.A.H., L.N., D.O., E.J.C., M.L.), The University of Manchester, Manchester, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing, China (R.-P.X.); and Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL (Y.K., R.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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