Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Eur J Heart Fail. 2009 Aug;11(8):739-48. doi: 10.1093/eurjhf/hfp094.
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).
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).
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.
磷酸肌醇 3 激酶（PI3K）的激活对于细胞生长至关重要，与适应性和失调性心肌肥厚有关。这项纵向犬研究旨在研究 PI3Kalpha 和 PI3Kgamma 在充血性心力衰竭（CHF）和心脏恢复（CR）期间心脏重构中的作用。
所有犬均接受手术治疗。通过心脏起搏诱导 CHF 3-4 周，起搏诱导 HF 后 5-6 周终止起搏允许 CR。对照犬接受假手术，但不进行起搏。CHF 时左心室（LV）收缩功能下降，CR 时恢复至正常水平的 80-90%，LV 重量增加 25%。CHF 时 PI3Kgamma 的表达增加了四倍，但在 CR 时恢复至对照水平。相比之下，CHF 时 PI3Kalpha 的表达与对照无差异，但在 CR 时增加了三倍，并伴有 Akt（五倍）、GSK-3beta（五倍）、β-catenin（三倍）、mTOR（两倍）和 P70S6K（两倍）的磷酸化增加。
我们的结果表明，PI3K 同工型在 CHF/CR 过程中受到不同的调节，PI3Kalpha 的选择性激活，通过 Akt、GSK-3beta 和 mTOR 信号通路，可能参与心脏代偿性肥厚的发展和功能恢复。
