title: Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways.
abstract: BACKGROUND
  It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1beta has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined.
  
  
  OBJECTIVE
  We studied the role of hypertrophy signal-mediated IL-1beta/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure.
  
  
  RESULTS
  Pressure overload was performed by aortic banding in IL-1beta-deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1beta-deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (approximately 50%) decreased in the IL-1beta-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1beta and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1beta-deficient CFs. IL-1beta released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1beta activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1beta deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them.
  
  
  CONCLUSIONS
  We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1beta, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602-8566 Japan.
authors.forename: Shoken
authors.initials: S
authors.lastname: Honsho
authors.forename: Susumu
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Amano
authors.forename: Kan
authors.initials: K
authors.lastname: Zen
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Eigo
authors.initials: E
authors.lastname: Kishita
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsui
authors.forename: Asako
authors.initials: A
authors.lastname: Katsume
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Okigaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; D050799:STAT5 Transcription Factor; D007334:Insulin-Like Growth Factor I; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases