Abstract 12381: Ast-120, an Adsorbent of Uremic Toxins Normalized the Cardiac Hypertrophic/pro- Apoptotic And Cardioprotective/anti-apoptotic Signaling in Pacing-induced Heart Failure in Dogs

Abstract

Background: Renal dysfunction increases the plasma levels of indoxyl sulfate (IS), a uremic toxin excreted from the kidney. Interestingly, IS is reported to directly stimulate both collagen synthesis and cardiomyocyte hypertrophy in vitro via the modulation of ERK and p38-MAPK. However, it is unclear whether the pathophysiology of heart failure (HF) changes such intracellular signaling via the IS-dependent pathways. AST-120 is known to inhibit the uptake of indole and decrease the plasma IS levels. Hypothesis: We tested the hypothesis that the removal of plasma IS by using AST-120 modulates the intracellular signaling for hypertrophy, collagen synthesis and apoptosis of the myocardium in the canine HF model in vivo. Method: A canine HF model was produced by continuous rapid ventricular pacing at 230 bpm for 6 weeks. We treated the canine with oral AST-120 (1g/kg/day) administration between 4th and 6th week following the onset of rapid pacing (HF with AST-120 group, HF without AST-120 group, n=7 in each). We also set a control (Control group, n=7) without pacing for 6 weeks. We extracted the protein from the hearts and analyzed it by Western blotting. Result: AST-120 treatment reduced both plasma IS elevated in the canine HF model. HF without AST-120 group showed the activation of ERK signaling and the deactivation of both Akt and p38-MAPK signaling compared with Control group. The treatment with AST-120 increased the phosphorylation levels of Akt and p38-MAPK, and suppressed the ERK phosphorylation. HF without AST-120 group also showed an increased expression of pro-apoptotic Bax protein, and a decreased expression of anti-apoptotic Bcl-2 protein. The increased Bcl-2/Bax ratio was significantly ameliorated by AST-120 treatment. Conclusion: The decreases in plasma levels of indoxyl sulfate by the treatment with AST-120 1) deactivates the cardiac hypertrophic signaling, 2) activates the cardiac survival and anti-apoptotic signals and 3) suppresses the pro-apoptotic signals in failing heart in vivo. Indoxyl sulfate may become a sensitive and novel biomarker/mediator of heart failure explaining the cardio-renal syndrome that links renal dysfunction to heart failure.