Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes

Jing Pan, Keiichi Fukuda, Mikiyoshi Saito, Junichi Matsuzaki, Hiroaki Kodama, Motoaki Sano, Toshiyuki Takahashi, Takahiro Kato, Satoshi Ogawa

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256 Citations (Scopus)


This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2/STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis- inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch- activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch- induced activation of this pathway, and protein kinase C was also partially involved in this activation.

Original languageEnglish
Pages (from-to)1127-1136
Number of pages10
JournalCirculation research
Issue number10
Publication statusPublished - 1999 May 28


  • Angiotensin II
  • Cardiac hypertrophy
  • Glycoprotein 130
  • JAK/STAT pathway
  • Mechanical stretch

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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