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Comment
. 2005 Aug;115(8):2059-64.
doi: 10.1172/JCI25900.

Akt1 in the cardiovascular system: friend or foe?

Brian T O'Neill  1 , E Dale Abel
Affiliations
Comment

Akt1 in the cardiovascular system: friend or foe?

Brian T O'Neill et al. J Clin Invest. 2005 Aug.

Abstract

Akt is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. Akt activation has been proposed as a potential strategy for increasing cardiomyocyte survival following ischemia. In mammalian cells, 3 distinct isoforms of Akt exist, but their precise roles in cardiovascular biology were previously unknown. Three separate studies published in this issue of the JCI now provide important new insight into the central role of Akt1 in the regulation of angiogenesis and the maladaptive or deleterious consequences of chronic unregulated Akt activation in the heart (see the related articles beginning on pages 2108, 2119, and 2128). Here we discuss the implications of these exciting new studies.

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Figures

Figure 1
Figure 1
Effect of short-term or long-term Akt activation in cardiac muscle. (A) Short-term activation of Akt1 by physiological stimuli, such as insulin and IGF-1 signaling or exercise, promotes physiologic cardiac hypertrophy. Insulin and IGF-1 signaling is mediated in part via tyrosine phosphorylation (P) of IRS-1/2. Phosphorylated IRS-1/2 associates with and activates PI3K, which stimulates the generation of phosphoinositide-3,4,5 triphosphate and subsequently leads to the activation of Akt. Akt1 promotes physiologic hypertrophy via mTOR-mediated pathways. Short-term activation is associated with increased VEGF generation and release and may also protect against I/R injury. (B) Long-term, high-level Akt signaling is maladaptive. Downregulation of IRS-1/2 proteins occurs via mechanisms that involve increased proteasomal degradation. It is believed that increased serine phosphorylation of IRS-1/2 will promote this degradation. In addition, serine phosphorylation of IRS-1/2 limits its association with the insulin receptor, which further reduces the activation of PI3K. Reduced PI3K activation is associated with reduced recovery and increased tissue injury following I/R due to loss of PI3K-dependent but Akt-independent cardioprotective mechanisms. It is also possible that reduced IRS-1_mediated PI3K signaling may contribute to cardiac injury in patients with dilated cardiomyopathy. Long-term activation of Akt continues to promote cardiac hypertrophy. However, there is downregulation of VEGF expression, which leads to reduced angiogenesis. A mismatch between cardiomyocyte growth and blood vessel growth leads to cell death and fibrosis. Ub, ubiquitination.
Figure 2
Figure 2
Akt1 promotes adaptive angiogenesis. In endothelial cells and VSMCs, Akt1 represents the predominant isoform. VEGF-mediated angiogenesis requires Akt1 activation. Angiogenesis is mediated in part by Akt1-dependent activation of eNOS, which leads to increased NO production. VEGF also phosphorylates glycogen synthase kinase_3β (GSK3β) and FOXO1, both of which may also contribute to Akt1-dependent angiogenesis. Akt1 is also required for the recruitment of bone marrow_derived endothelial precursor cells to sites of ischemia and for the migration of mature endothelial cells and fibroblasts to areas of active new vessel formation. Note that although Akt2 is expressed in fibroblasts, its expression is not required for promoting fibroblast migration. Akt1-mediated cross-talk between endothelium and cardiomyocyte involves the release of VEGF from cardiomyocytes, which may influence the vascular response to hypertrophy. It is also likely that Akt1-mediated release of NO from the vasculature will have important regulatory effects on the cardiomyocyte.
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