title: Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice.
abstract: BACKGROUND
  Although numerous signaling pathways are known to be activated in experimental cardiac hypertrophy, the molecular basis of the hypertrophic response inherent in human heart diseases remains largely unknown. Integrin-linked kinase (ILK) is a multifunctional protein kinase that physically links beta-integrins with the actin cytoskeleton, suggesting a potential mechanoreceptor role.
  
  
  RESULTS
  Here, we show a marked increase in ILK protein levels in hypertrophic ventricles of patients with congenital and acquired outflow tract obstruction. This increase in ILK was associated with activation of the Rho family guanine triphosphatases, Rac1 and Cdc42, and known hypertrophic signaling kinases, including extracellular signal-related kinases (ERK1/2) and p70 S6 kinase. Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK(S343D)) or wild-type ILK (ILK(WT)) exhibited a compensated ventricular hypertrophic phenotype and displayed an activation profile of guanine triphosphatases and downstream protein kinases concordant with that seen in human hypertrophy. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactive ILK (ILK(R211A)) were unable to mount a compensatory hypertrophic response to angiotensin II in vivo.
  
  
  CONCLUSIONS
  Taken together, these results identify ILK-regulated signaling as a broadly adaptive hypertrophic response mechanism relevant to a wide range of clinical heart disease.
authors.affiliation: Cancer Research Program, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Lu
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Dai
authors.forename: Changqing
authors.initials: C
authors.lastname: Du
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.forename: Perry S
authors.initials: PS
authors.lastname: Mongroo
authors.forename: Arthur
authors.initials: A
authors.lastname: Lau
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yamabi
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Gregory
authors.initials: G
authors.lastname: Hannigan
authors.forename: John G
authors.initials: JG
authors.lastname: Coles
mesh_terms: D000409:Alanine; D000804:Angiotensin II; D000818:Animals; D001120:Arginine; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005333:Fetus / Q000201:enzymology; D006352:Heart Ventricles; D006801:Humans; D007223:Infant; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D014694:Ventricular Outflow Obstruction / Q000151:congenital / Q000201:enzymology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000409:Alanine; D000804:Angiotensin II; D001120:Arginine; D048049:Extracellular Signal-Regulated MAP Kinases; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK