ACTIVATION OF GP130 TRANSDUCES HYPERTROPHIC SIGNALS VIA STAT3 IN CARDIAC MYOCYTES

Background-gp130, a signal transducer of the IL-6-related cytokines, i s expressed ubiquitously, including in the heart. The activation of gp 130 in cardiac myocytes was reported to induce myocardial hypertrophy. The downstream side of gp130 consists of two distinct pathways in car diac myocytes, one a Janus kinase/signal transducer and activator of t ranscription (JAK/STAT) pathway, the other a mitogen-activated protein kinase (MAPK) pathway. In the present study, we examined whether the JAK/STAT pathway, especially the STAT3-mediated pathway, plays a criti cal role in gp130-dependent myocardial hypertrophy by transfecting wil d-type and mutated-type STAT3 cDNA to cardiac myocytes. Methods and Re sults-We constructed three I;inds of replication-defective adenovirus vectors carrying wild-type (AD/WT) or mutated-type (AD/DN) STAT3 cDNA or adenovirus vector itself (AD). Cultured murine cardiac myocytes inf ected with adenovirus were stimulated with leukemia inhibitory factor (LIF), and the expression of c-Sos and atrial natriuretic factor (ANF) mRNAs and [H-3]leucine incorporation were examined. There were no sig nificant differences in MAPK activity among the three groups. Compared with AD-transfected cardiac myocytes, induction of c-Sos and ANF mRNA s and protein synthesis after LIF stimulation were significantly augme nted in AD/WT-transfected cells. In contrast, induction of c-Sos and A NF mRNA expression and protein synthesis were attenuated after LIF sti mulation in cardiac myocytes transfected with AD/DN. Conclusions-These results suggest that the STAT3-dependent signaling pathway downstream of gp 130 promotes cardiac myocyte hypertrophy under stimulation with LIF.