Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase α in mouse

Abstract

Background Use of low doses of digitalis to prevent the development of heart failure was advocated decades ago, but conflicting results of early animal studies dissuaded further research on this issue. Recent discoveries of digitalis effects on cell signal pathways prompted us to reexamine the possibility of this prophylactic action of digitalis. The specific aim of the present study was to determine if subinotropic doses of ouabain would prevent pressure overload-induced cardiac remodeling in the mouse by activating phosphoinositide 3-kinase α (PI3Kα).ResultsStudies were done on an existing transgenic mouse deficient in cardiac PI3Kα (p85-KO) but with normal cardiac contractility, a control mouse (Con), and on cultured adult cardiomyocytes. In Con myocytes, but not in p85-KO myocytes, ouabain activated PI3Kα and Akt, and caused cell growth. This occurred at low ouabain concentrations that did not activate the EGFR-Src/Ras/Raf/ERK cascade. Con and p85-KO mice were subjected to transverse aortic constriction (TAC) for 8 weeks. A subinotropic dose of ouabain (50 µg/kg/day) was constantly administrated by osmotic mini-pumps for the first 4 weeks. All mice were monitored by echocardiography throughout. Ouabain early treatment attenuated TAC-induced cardiac hypertrophy and fibrosis, and improved cardiac function in TAC-operated Con mice but not in TAC-operated p85-KO mice. TAC downregulated α2-isoform of Na+/K+-ATPase but not its α1-isoform in Con hearts, and ouabain treatment prevented the downregulation of α2-isoform. TAC-induced reduction of α2-isoform did not occur in p85-KO hearts.ConclusionsOur results show that (a) safe doses of ouabain prevent or delay cardiac remodeling of pressure overloaded mouse heart; and (b) these prophylactic effects are due to ouabain binding to α2-isoform resulting in the selective activation of PI3Kα. Our findings also suggest that potential prophylactic use of digitalis for prevention of heart failure in man deserves serious consideration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0053-7) contains supplementary material, which is available to authorized users.

[Retracted] Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway

“…In our study, higher FOXO3 and Beclin expressions were observed in rabbits with HF compared with those in the control group, and CCM signals application significantly decreased their expressions (Figure 3). Wu et al [26] reported that the activation of Pi3k expressions in the mouse heart could prevent cardiac remodeling. In this study, lower Pi3k expressions were observed in the HF group than in the control group, and their concentrations significantly increased in the CCM and (e) western blot images of mTOR, p-mTOR, GSK-3β, and TORC2.…”

Ischemia/reperfusion-induced alterations of enzymatic and signaling functions of the rat cardiac Na+/K+-ATPase: protection by ouabain preconditioning

“…; Wu et al. ). The most documented example of protection against ischemia‐reperfusion injury by a CG is ouabain preconditioning (OPC).…”

“…Ouabain binding to the a-subunit of Na + /K + -ATPase also initiates specific intracellular signaling pathways, most notably PI3K/Akt and c-Src/ERK in the cardiac tissue of various species (Mohammadi et al 2001(Mohammadi et al , 2003Liu et al 2007; Morgan et al 2010;Bai et al 2013;Duan et al 2015). Based on experimental evidence reported in recent years, the concept that these intracellular events occur at low (subinotropic) concentration and lead to additional cardiac actions of CG such as hypertrophic growth, prevention of cardiac hypertrophy and failure, and protection against ischemia-reperfusion injury has emerged (Liu et al 2007;Pasdois et al 2007;Pierre et al 2007;D'Urso et al 2008;Morgan et al 2010;Bai et al 2013;Belliard et al 2013;Duan et al 2015;Wu et al 2015). The most documented example of protection against ischemia-reperfusion injury by a CG is ouabain preconditioning (OPC).…”

Ouabain - A gift from paradise

“…In rat and rabbit hearts short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. Current reports confirm cardio protection induced by ouabain [9]. It is suggested that ouabain can be beneficial to various stages of heart failure [10].…”