Aims : Although increased levels of myocardial receptor activator of NF-觀B ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodeling is less well understood. This study sought to determine the relationship between early cardiac remodeling in pressure overload, RANKL expression and induction of inflammatory cytokines. Methods and Results : A marked increase in RANKL expression occurred as early as six-hour following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 14 days. An increase in TNF-慣, IL-1慣, and IL-1棺 was observed in the hypertrophied hearts only at 3 or 14 days after TAC. Treatment with losartan significantly attenuated TAC-induced cardiac hypertrophy, in parallel with decreased expression of RANKL, TNF-慣, IL-1慣, and IL-1棺. RANKL stimulated a 5- to 10-fold induction in TNF-慣, IL-1慣, and IL-1棺 mRNA expression in neonatal rat cardiomyocytes (NRCMs) via activation of the transcription factor, NF-觀B. RANKL-induced NF-觀B activation and expression of these cytokines were both attenuated when TRAF2 or TRAF6, adaptors for RANK, was silenced by siRNA. Furthermore, inhibitors of phospholipase C (PLC), protein kinase C (PKC), and I觀B kinase also significantly inhibited RANKL-induced cellular activities, but inhibitors of phosphatidylinositol 3-kinase (PI3K), ERK1/2, or p38 MAPK were without effect. Conclusion : Our data demonstrate for the first time that the pressure overloaded myocardium generates RANKL, which potentially induces TNF-慣, IL-1慣, and IL-1棺 production via a TRAF2/TRAF6-PLC-PKC-NF-觀B mediated autocrine mechanism.