FoxO, autophagy, and cardiac remodeling

Abstract

In response to changes in workload, the heart grows or shrinks. Indeed, the myocardium is capable of robust and rapid structural remodeling. In the setting of normal, physiological demand, the heart responds with hypertrophic growth of individual cardiac myocytes, a process that serves to maintain cardiac output and minimize wall stress. However, disease-related stresses, such as hypertension or myocardial infarction, provoke a series of changes that culminate in heart failure and/or sudden death. At the other end of the spectrum, cardiac unloading, such as occurs with prolonged bed rest or weightlessness, causes the heart to shrink. In recent years, considerable strides have been made in deciphering the molecular and cellular events governing pro- and anti-growth events in the heart. Prominent among these mechanisms are those mediated by FoxO (Forkhead box-containing protein, O subfamily) transcription factors. In many cell types, these proteins are critical regulators of cell size, viability, and metabolism, and their importance in the heart is just emerging. Also in recent years, evidence has emerged for a pivotal role for autophagy, an evolutionarily conserved pathway of lysosomal degradation of damaged proteins and organelles, in cardiac growth and remodeling. Indeed, evidence for activated autophagy has been detected in virtually every form of myocardial disease. Now, it is clear that FoxO is an upstream regulator of both autophagy and the ubiquitin-proteasome system. Here, we discuss recent advances in our understanding of cardiomyocyte autophagy, its governance by FoxO, and the roles each of these plays in cardiac remodeling.

Fig. 1

FoxO activity is regulated by multiple posttranslational modification events. Insulin/IGF-1 activates the insulin receptor to recruit the PI3K/PDK complex which, in turn, phosphorylates Akt/SGK leading to FoxO phosphorylation and nuclear exclusion via 14-3-3- and Crm-1-dependent mechanisms. Cytoplasmic FoxO can be phosphorylated by IKKβ and ERK1/2, leading to FoxO polyubiquitylation by Skp2 and an unknown E3 ligase, and subsequent proteasomal degradation. On exposure to oxidative stress, phosphorylation of FoxO by JNK/MST1 and monoubiquitylation by an unknown E3 ligase promote FoxO nuclear translocation to potentiate its transcriptional activity. Stress-induced deacetylation of FoxO by Sirt1 counteracts p300/CBP-dependent FoxO inactivation and results in prolonged FoxO promoter occupancy. Concomitantly, deubiquitylases (e.g. USP7) and phosphatases (PPase) antagonize these pathways

Fig. 2

FoxO governs the autophagic pathway at multiple steps. Numerous stimuli, such as starvation and oxidative stress, activate the class III PI3 kinase/Beclin 1/Atg14 complex to trigger the autophagic process. First, an isolated, double-membrane structure (phagophore) is formed (nucleation) followed by membrane elongation and substrate recognition. This is followed by Atg8 lipidation, cargo engulfment, and membrane fusion to form the distinctive double-membrane autophagosome. The autophagosome then fuses with a lysosome to form an autolysosome where the engulfed substrate is degraded. The resulting small molecule by-products, including amino acids, energy mediators, and lipids, are released, providing fuel to preserve cellular function and viability. The transcriptional activity of FoxO regulates expression of several autophagy-related genes (ATGs) that participate in autophagy at multiple points

Fig. 3

Graded levels of autophagic activity, each regulated by FoxO, contribute importantly to cardiac homeostasis and disease. Under physiological conditions, basal autophagic activity participates in protein quality control, efficiently removing damaged proteins and organelles, and recycling each element. Under conditions of mild stress and during ageing, FoxO factors induce the expression of diverse genes to detoxify ROS and eliminate damaged proteins and organelles, thereby promoting stress responsiveness. In the setting of severe or chronic stress, such as biomechanical load (e.g. hypertension), autophagy is activated yet further, which can lead to cellular demise and consequent heart failure. In other instances, such as ventricular unloading (e.g. prolonged bed rest), increased catabolic activity through both autophagy- and proteasome-mediated protein degradation reduces myocyte size, leading to cardiac atrophy. Complete abrogation of autophagic activity in the myocyte through inactivation of critical autophagy-related genes is also maladaptive, triggering rapid cardiac dysfunction