Selective activation of PI3K
/Akt/GSK-3β signalling and cardiac compensatory hypertrophy during recovery from heart failure
1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
2 Molecular Cardiology, Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH 44195, USA
3 Institute of Molecular and Experimental Therapeutics, East China Normal University, Shanghai, China
* Corresponding author. Email: wqshen2003{at}hotmail.com
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Abstract |
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Aims: Activation of phosphoinositide-3 kinase (PI3K) is essential for cell growth, relating to adaptive and maladaptive cardiac hypertrophy. This longitudinal canine study was designed to investigate the role of PI3K
and PI3K
in cardiac remodelling during congestive heart failure (CHF) and cardiac recovery (CR).
Methods and results: All dogs were surgically instrumented. Congestive heart failure was induced by cardiac pacing for 3–4 weeks and CR was allowed by terminating pacing for 5–6 weeks after induction of HF. Control dogs had sham surgery, but did not undergo pacing. Left ventricular (LV) contractile function was depressed in CHF and restored to 80–90% of the normal level in CR, with a 25% increase in LV weight. The expression of PI3K was increased four-fold in CHF, but returned to control levels in CR. In contrast, the expression of PI3K in CHF was not different from that in controls, but increased three-fold in CR and was accompanied by increases in phosphorylation of Akt (five-fold), GSK-3β (five-fold), β-catenin (three-fold), mTOR (two-fold), and P70S6K (two-fold).
Conclusion: Our results indicate that PI3K isoforms are regulated differently during the course of CHF/CR and that the selective activation of PI3K, through Akt, GSK-3β, and mTOR signalling pathways, may be involved in the development of cardiac compensatory hypertrophy and functional restoration.
Key Words: PI3K • PI3K • Heart failure • Cardiac recovery • Cardiac hypertrophy
Received January 9, 2009; Revised April 15, 2009; Accepted May 14, 2009