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.
abstract: 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.
  
  
  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-β 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.
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Zi
authors.forename: Hoyee
authors.initials: H
authors.lastname: Tsui
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: Leo
authors.initials: L
authors.lastname: Zeef
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
authors.forename: Mark
authors.initials: M
authors.lastname: Travis
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.forename: Andrew
authors.initials: A
authors.lastname: Berry
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Ke
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000187:drug effects* / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017725:Ventricular Pressure
chemical_list: D015815:Cell Adhesion Molecules; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C082838:Postn protein, mouse; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: FTY-720; NFAT; cardiac hypertrophy; fibrosis; periostin