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

• Published in: Cell & bioscience Vol. 5; no. 56
• Main Authors: Wu, Jian, Li, Daxiang, Du, Lingling, Baldawi, Mustafa, Gable, Marjorie E, Askari, Amir, Liu, Lijun
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 18.11.2015
• Subjects: Adenosine triphosphatase; Cardiac glycosides; Cardiotonic agents; Cellular signal transduction; Genetic engineering; Heart; Heart enlargement; Heart failure; Ouabain; Prevention
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-015-0053-7

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 [alpha] (PI3K[alpha]). Studies were done on an existing transgenic mouse deficient in cardiac PI3K[alpha] (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 PI3K[alpha] 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 [micro]g/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 [alpha]2-isoform of Na.sup.+/K.sup.+-ATPase but not its [alpha]1-isoform in Con hearts, and ouabain treatment prevented the downregulation of [alpha]2-isoform. TAC-induced reduction of [alpha]2-isoform did not occur in p85-KO hearts. Our 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 [alpha]2-isoform resulting in the selective activation of PI3K[alpha]. Our findings also suggest that potential prophylactic use of digitalis for prevention of heart failure in man deserves serious consideration.