AKT signalling in the failing heart

Abstract

AKT is a serine/threonine protein kinase, also known as protein kinase B, which regulates cardiac growth, myocardial angiogenesis, glucose metabolism, and cell death in cardiac myocytes. AKT is activated by its phosphorylation at Thr 308 and ser 473 by PDK1 and mTORC2, respectively, in response to trophic stimuli such as insulin and insulin growth factor. c-Jun N-Terminal Kinases (JNKs) phosphorylate AKT at Thr 450 and potentiate its interaction with its downstream effectors. The short-term activation of AKT promotes physiological hypertrophy and protection from myocardial injury; whereas, its long-term activation causes pathological hypertrophy and heart failure. In this review we will discuss the role of AKT in regulating signalling pathways in the heart with special emphasis on the role of AKT in modulating stress induced autophagic cell death in cardiomyocytes in vitro.

Figure 1

AKT signalling in the heart. The short-term activation of AKT protects the cardiomyocyte against environmental stressors via the inhibition of cell death and the promotion of cell growth and cardiac angiogenesis. The short-term activation of JNK is cardioprotective as well. JNK phosphorylates AKT at threonine 450 and potentiates its interaction with its downstream effectors. It remains unclear as to why these favourable effects of AKT are lost with its prolonged activation. One hypothesis is that other signalling pathways dominate and override the interaction of AKT with its downstream effectors. This hypothesis clearly needs to be investigated in the future. IGF-R, insulin-like growth factor receptor; PI3K1, phosphatidylinositol 3-kinase 1; mTORC2, mammalian target of rapamycin 2; 3 MA, 3-methyladenine; PKC, protein kinase C; JNK, c-Jun N-terminal kinases; green arrows, promote signalling pathway; red arrows, inhibit signalling pathway.