title: 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).
  
  
  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.
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA ; Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA ; State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, People's Republic of China.
authors.forename: Daxiang
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Baldawi
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA.
authors.forename: Marjorie E
authors.initials: ME
authors.lastname: Gable
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Askari
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Ave., MS 1010, Toledo, OH 43614 USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
keywords: Cardiac hypertrophy; Digitalis; Heart failure; Na+/K+-ATPase; Ouabain; PI3 kinase