Key result
Digoxin increases PPARδ expression and TnI phosphorylation in high-glucose H9c2 cells via calcium signaling.
Why the study?
The cellular mechanisms by which digoxin increases PPARδ expression in cardiac cells under high glucose conditions were not elucidated.
Should not change digoxin use in heart failure; leaves open PPARδ mechanisms in diabetic cardiomyopathy pending clinical studies.
BACKGROUND AND PURPOSE: Digoxin has been used as an inotropic agent in heart failure for a long time. Troponin I (TnI) phosphorylation is related to cardiac contractility, and the genes are regulated by peroxisome proliferator-activated receptors (PPARs). Our previous studies indicated that cardiac abnormality related to the depressed expression of PPARδ in the hearts of STZ rats is reversed by digoxin. However, the cellular mechanisms for this effect of digoxin have not been elucidated. The aim of the present study was to investigate possible mechanisms for this effect of digoxin using the H9c2 cell line cultured in high glucose (HG) conditions. METHODS: The effects of digoxin on PPARδ expression, intracellular calcium and TnI phosphorylation were investigated in cultured H9c2 cells, maintained in a HG medium, by using Western blot analysis. RESULTS: Digoxin increased PPARδ expression in H9c2 cells subjected to HG conditions, and increase the intracellular calcium concentration. This effect of digoxin was blocked by BAPTA-AM at concentrations sufficient to chelate calcium ions. In addition, the calcineurin inhibitor cyclosporine A and KN93, an inhibitor of calcium/calmodulin-dependent protein kinase, inhibited this action. Digoxin also increased TnI phosphorylation and this was inhibited when PPARδ was silenced by the addition of RNAi to the cells. Similar changes were observed on the contraction of H9c2 cells. CONCLUSION: The results suggest that digoxin appears, through calcium-triggered signals, to reverse the reduced expression of PPARδ in H9c2 cells caused by HG treatment.
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Chen et al. (2011) studied High glucose conditions (in vitro model). Digoxin vs. High glucose conditions without digoxin or with inhibitors was evaluated on PPARδ expression, intracellular calcium, and TnI phosphorylation. Digoxin increased PPARδ expression and TnI phosphorylation in H9c2 cells under high glucose conditions via calcium-triggered signals.
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