Background
Use of low doses of digitalis to prevent the development of heart failure was advocated decades ago, but conflicting
Conclusions
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 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.
Results
Studies 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. Conclusions: 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 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.