Regulation of myofibroblast differentiation by cardiac glycosides

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Abstract

Myofibroblast differentiation is a key process in pathogenesis of fibrotic diseases. Cardiac glycosides (ouabain, digoxin) inhibit Na+-K+-ATPase, resulting in increased intracellular [Na+]-to-[K+] ratio in cells. Microarray analysis suggested that increased intracellular [Na+]/[K+] ratio may promote the expression of cyclooxygenase-2 (COX-2), a critical enzyme in the synthesis of prostaglandins. Given antifibrotic effects of prostaglandins through activation of protein kinase A (PKA), we examined if cardiac glycosides stimulate COX-2 expression in human lung fibroblasts and how they affect myofibroblast differentiation. Ouabain stimulated a profound COX-2 expression and a sustained PKA activation, which was blocked by COX-2 inhibitor or by COX-2 knockdown. Ouabain-induced COX-2 expression and PKA activation were abolished by the inhibitor of the Na+/Ca2+ exchanger, KB-R4943. Ouabain inhibited transforming growth factor-β (TGF-β)-induced Rho activation, stress fiber formation, serum response factor activation, and the expression of smooth muscle α-actin, collagen-1, and fibronectin. These effects were recapitulated by an increase in intracellular [Na+]/[K+] ratio through the treatment of cells with K+-free medium or with digoxin. Although inhibition of COX-2 or of the Na+/Ca2+ exchanger blocked ouabain-induced PKA activation, this failed to reverse the inhibition of TGF-β-induced Rho activation or myofibroblast differentiation by ouabain. Together, these data demonstrate that ouabain, through the increase in intracellular [Na+]/[K+] ratio, drives the induction of COX-2 expression and PKA activation, which is accompanied by a decreased Rho activation and myofibroblast differentiation in response to TGF-β. However, COX-2 expression and PKA activation are not sufficient for inhibition of the fibrotic effects of TGF-β by ouabain, suggesting that additional mechanisms must exist.

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La, J., Reed, E. B., Koltsova, S., Akimova, O., Hamanaka, R. B., Mutlu, G. M., … Dulin, N. O. (2016). Regulation of myofibroblast differentiation by cardiac glycosides. American Journal of Physiology - Lung Cellular and Molecular Physiology, 310(9), L815–L823. https://doi.org/10.1152/ajplung.00322.2015

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