title: Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy.
abstract: BACKGROUND
  We examined the role of Jak2 kinase phosphorylation in the development of pressure overload hypertrophy in mice subjected to transverse aortic constriction (TAC) and treated with tyrphostin AG490, a pharmacological inhibitor of Jak2.
  
  
  METHODS
  Control mice (sham), subjected to TAC for 15 days (TAC) or to TAC and treated with 48 microg/kg/day i.p. of tyrphostin AG490 (TAC+AG490) were evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy.
  
  
  RESULTS
  Mice subjected to TAC alone developed concentric hypertrophy that accompanied activation of the components of the Jak/STAT signaling pathway manifested by an increase in phosphorylation of Jak2 and STAT3. We also observed increased phosphorylation of MAPK p44/p42, p38 MAPK and JNK in the TAC group, as well as, an increase in expression of MKP-1 phosphatase which negatively regulates MAPK kinases. Treatment of aortic constricted mice with tyrphostin AG490 failed to develop hypertrophy and showed a marked reduction in phosphorylation of Jak2 and STAT3. There was, however, in TAC and AG490 treated mice, a notable increase in the phosphorylation state of the MAPK p44/42, whereas MKP-1 phosphatase was downregulated.
  
  
  CONCLUSIONS
  These findings suggest that Jak2 kinase plays an important role in left ventricular remodeling during pressure overload hypertrophy. Pharmacological inhibition of Jak2 kinase during pressure overload blocks the development of concentric hypertrophy.
authors.affiliation: Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave. Brooklyn, NY 11203, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Beckles
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mascareno
authors.forename: M A Q
authors.initials: MA
authors.lastname: Siddiqui
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects; D024723:Ventricular Myosins / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000199:Actins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D009320:Atrial Natriuretic Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D024723:Ventricular Myosins