Selective activation of PI3Kalpha/Akt/GSK-3beta signalling and cardiac compensatory hypertrophy during recovery from heart failure.
OBJECTIVE
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 PI3Kalpha and PI3Kgamma in cardiac remodelling during congestive heart failure (CHF) and cardiac recovery (CR).


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 PI3Kgamma was increased four-fold in CHF, but returned to control levels in CR. In contrast, the expression of PI3Kalpha 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-3beta (five-fold), beta-catenin (three-fold), mTOR (two-fold), and P70S6K (two-fold).


CONCLUSIONS
Our results indicate that PI3K isoforms are regulated differently during the course of CHF/CR and that the selective activation of PI3Kalpha, through Akt, GSK-3beta, and mTOR signalling pathways, may be involved in the development of cardiac compensatory hypertrophy and functional restoration.
Braz
Julian C
JC
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Gill
Robert M
RM
Corbly
Angela K
AK
Jones
Bonita D
BD
Jin
Najia
N
Vlahos
Chris J
CJ
Wu
Qingyu
Q
Shen
Weiqun
W
D000704:Analysis of Variance; D000818:Animals; D004280:Dobutamine; D004285:Dogs; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D023421:Models, Animal; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D015398:Signal Transduction
D012333:RNA, Messenger; D004280:Dobutamine; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3