title: Deep sequence analysis of gene expression identifies osteopontin as a downstream effector of integrin-linked kinase (ILK) in cardiac-specific ILK knockout mice.
abstract: BACKGROUND
  Integrin-linked kinase (ILK) is a serine/threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood.
  
  
  RESULTS
  To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice using α-myosin heavy chain-driven Cre expression. Cardiac-specific ILK knockout mice spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression to compare comprehensive transcriptional profiles of cardiac-specific ILK knockout and wild-type hearts from 10-day-old mice before the development of cardiac dysfunction. Approximately 2×10(6) cDNA clones from each genotype were sequenced, corresponding to 33 274 independent transcripts. A total of 93 genes were altered, using nominal thresholds of >1.4-fold change and P<0.001. The most highly upregulated gene was osteopontin (47-fold increase; P=9.6×10(-45)), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in cardiac-specific ILK knockout mice.
  
  
  CONCLUSIONS
  Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
authors: Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA.
authors: Jing
authors: J
authors: Dai
authors: Takashi
authors: T
authors: Matsui
authors: E Dale
authors: ED
authors: Abel
authors: Shoukat
authors: S
authors: Dedhar
authors: Robert E
authors: RE
authors: Gerszten
authors: Christine E
authors: CE
authors: Seidman
authors: J G
authors: JG
authors: Seidman
authors: Anthony
authors: A
authors: Rosenzweig
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D053495:Osteopontin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D000099200:Scaffold Protein ILK
chemical_list: D000906:Antibodies; D053495:Osteopontin; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
keywords: cardiomyopathy, dilated; gene expression profiling; integrin-linked kinase; osteopontin