Abstract 17436: STAT3 Inhibition Protects Against Cardiomyocyte Hypertrophy Through a Novel NF-kB p65/Nrf2/HO-1 Pathway

Introduction: Left ventricular hypertrophy is the end-result of diverse cardiovascular pathologies. STAT3 signaling has been implicated in cardiomyocyte hypertrophy, although the precise mechanism remains incompletely understood. Hypothesis: We hypothesized that STAT3 induces myocyte hypertrophy via NF-kB/Nrf2 pathway. Methods and Results: Treatment of H9c2 cells with 1 μM Angiotensin II for 48 h induced a 2.4-fold increase in cell size compared with controls. This cellular hypertrophy was significantly inhibited in the presence of STAT3 inhibitor WP1066 (Figure). The levels of heme oxygenase-1 (HO-1), a key molecule in cardioprotective signaling, were increased by WP1066 treatment and decreased by STAT3 overexpression. Further investigation of the underlying mechanism revealed that WP1066 blocks the inhibitory effect of NF-kB p65 on Nrf2, leading to an upregulation of HO-1 (Figure). By using chromosome-IP and bioinformatics analysis, we identified that p65 suppresses Nrf2 expression by directly binding to the promoter region of Nrf2. The p65/Nrf2/HO-1 signaling pathway was further confirmed by using both p65 transient overexpression and NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC). Conclusions: We conclude that angiotensin II-induced cardiomyocyte hypertrophy involves STAT3 signaling and downstream components include p65, Nrf2, and HO-1. These novel molecular insights may lead to development of new therapy to prevent and treat cardiac hypertrophy.