Abstract 17746: Telecinobufagin, a Novel Cardiotonic Steroid, Promotes Myocardial and Renal Fibrosis via Na/K-ATPase Profibrotic Signalling Pathways
Cardiotonic steroids (CTS) are Na/K-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We recently discovered significantly elevated levels of a novel CTS, telocinobufagin (TCB), in patients with heart failure. We tested the hypothesis that TCB promotes cardiac and renal dysfunction in a process involving signaling through the NKA-α-1 in the following studies. First, we infused TCB (4 weeks at 10 ug/Kg/day) or vehicle into mice expressing wild type NKA-α-1 (WT), as well as mice with a genetic reduction of NKA-α-1 (NKA+/-) or transgenic human NKA-α-1 (NKA-Tg), which renders them more sensitive to CTS. TCB infusion resulted in impairment of cardiac structure (36% increase in heart weight/body weight ratio, 18% increase in diastolic Left Ventricular Internal Dimension vs. vehicle, p<0.05) in WT mice which was significantly attenuated in NKA+/- mice. TCB infusion also resulted increased proteinuria and cystatin C in WT mice which was significantly attenuated in NKA+/- mice (all p<0.05) despite similar increases in blood pressure. In NKA-Tg mice, TCB infusion resulted in increased myocardial (Fig 1A) and renal (Fig 1B) fibrosis vs. WT (all p<0.05). In a series of in vitro experiments, 24 hour treatment of HK2 renal proximal tubular cells with TCB resulted in significant dose dependent increases in both Collagen 1 and 3 mRNA (2 fold increases at 10 nM, 5 fold increases at 100 nM, p<0.05). TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc resulted in a 1.5 fold increase in Collagen 1 and 3 mRNA (p<0.05) as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p<0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p<0.05), while these effects were absent in SYF cells without Src kinase. These studies suggest that the pro-fibrotic effects of TCB are mediated though the NKA-Src kinase signaling pathway.
Author Disclosures: D.J. Kennedy: Research Grant; Modest; AHA SDG 14SDG18650010. M.E. Weber: None. A. Guggilam: None. K.M. Westfall: None. B. Agatisa-Boyle: None. P. Bucur: None. J.B. Lingrel: None. W. Tang: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.