Mechanical stretch activates the JAK STAT pathway in rat cardiomyocytes

This study was designed to determine whether mechanical stretch activates t he Janus kinase (JAK)/signal transducers and activators of transcription (S TAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/ murine cardiomyocytes were cultured on malleable silicone dishes and were s tretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and pe aked 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 (AT(1) blocker) partially inhibited the phosphor ylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothe lin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (ant i-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT 3 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+/c almodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stre tch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, a nd leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that th is activation was partially dependent on autocrine/paracrine-secreted angio tensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracell ular Ca2+ were necessary for stretch-induced activation of this pathway, an d protein kinase C was also partially involved in this activation.