title: Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart.
abstract: BACKGROUND
  Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy.
  
  
  RESULTS
  Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1(cko)). When subjected to 2 weeks of pressure overload, Pak1(cko) mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1(cko) mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1(cko) mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation.
  
  
  CONCLUSIONS
  These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.
authors.affiliation: Faculty of Life Sciences, School of Biomedicine, The 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: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Susanne
authors.initials: S
authors.lastname: Ulm
authors.forename: Jiawei
authors.initials: J
authors.lastname: Jin
authors.forename: Domenico M
authors.initials: DM
authors.lastname: Taglieri
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.forename: Junhong
authors.initials: J
authors.lastname: Gui
authors.forename: Hoyee
authors.initials: H
authors.lastname: Tsui
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Ke
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: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D000068876:Fingolimod Hydrochloride; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D050778:NFATC Transcription Factors / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013312:Stress, Physiological; D054462:p21-Activated Kinases / Q000172:deficiency / Q000187:drug effects* / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors; D011409:Propylene Glycols; D000804:Angiotensin II; D054462:p21-Activated Kinases; D048670:MAP Kinase Kinase 4; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
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