مورد إلكتروني
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.
| العنوان: | 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. |
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| بيانات النشر: | 2013 |
| تفاصيل مُضافة: | Liu, Wei Zi, Min Tsui, Hoyee Chowdhury, Sanjoy K. Zeef, Leo Meng, Qing-Jun Travis, Mark Prehar, Sukhpal Berry, Andrew Hanley, Neil A. Neyses, Ludwig Xiao, Rui-Ping Oceandy, Delvac Ke, Yunbo Solaro, R. John Cartwright, Elizabeth J. Lei, Ming Wang, Xin |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | BACKGROUND: 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. METHODS AND RESULTS: 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 (Gi-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-beta responsiveness and decrease collagen expression. CONCLUSIONS: 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. |
| مصطلحات الفهرس: | Animals, Animals, Newborn, Cardiomegaly/drug therapy, Cell Adhesion Molecules/drug effects/physiology, Cells, Cultured, Fibroblasts/cytology, Fibrosis, Hemodynamics/drug effects, Immunosuppressive Agents/pharmacology, Male, Mice, Mice, Inbred C57BL, Myocardium/pathology, NFATC Transcription Factors/drug effects/physiology, Propylene Glycols/pharmacology, Rats, Rats, Sprague-Dawley, Sphingosine/analogs & derivatives/pharmacology, Ventricular Pressure, FTY-720, NFAT, cardiac hypertrophy, fibrosis, periostin, info:eu-repo/semantics/article |
| URL: | |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | English |
| أرقام أخرى: | LULUX oai:orbilu.uni.lu:10993/17601 info:doi:10.1161/CIRCHEARTFAILURE.112.000123 WOS:000335157800034 PMID:23753531 SCOPUS_ID:84884719159 1134895209 |
| المصدر المساهم: | UNIV OF LUXEMBOURG From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1134895209 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |