Chapter Seventeen - Role of FoxO transcription factors in aging-associated cardiovascular diseases
Introduction
Aging is characterized by the gradual functional decline of various organ systems in the body with age. The heart, a highly metabolically active organ, is no exception and suffers from various aging-associated detrimental changes. Remarkably, aging constitutes a dominant risk factor for the development of cardiovascular diseases (CVDs), with their prevalence dramatically increasing with advancing age (North & Sinclair, 2012). Cardiac aging is characterized by a progressive decline in structure and function of heart as well as weakened stress-response (Dai, Chen, Johnson, Szeto, & Rabinovitch, 2012; Lee & Kim, 2018). The aging heart undergoes physiological changes such as left ventricular hypertrophy, muscle weakness, interstitial fibrosis, metabolic dysfunction, diastolic dysfunction, valvular degeneration, atrial fibrillation, and reduced maximal exercise capacity (Dai et al., 2012; Paneni, Diaz Canestro, Libby, Luscher, & Camici, 2017). In addition to intrinsic cardiac aging, old age increases the exposure to hypertension, diabetes, hypercholesterolemia and various other risk factors for CVDs (Dai et al., 2012). Collectively, these factors increase the prevalence of CVDs in the older population, thus increasing morbidity and mortality.
Research in the past decades have identified multiple genes and pathways that regulate aging and the development of aging-associated diseases. Among these, the Forkhead box O (FoxO) subfamily of the forkhead box family of transcription factors have gained increasing attention due to their crucial roles in regulating diverse cellular processes implicated in lifespan extension and aging (Martins, Lithgow, & Link, 2016). The Forkhead box (Fox) family of transcription factors consists of 19 different subfamilies designated A-S of which, the subfamily O consists of four isoforms, namely FoxO1, FoxO3a, FoxO4 and FoxO6 in the mammals which share a high degree of homology (Burgering, 2008; Kaestner, Knochel, & Martinez, 2000). Of these, the first three members have been shown to play critical roles in the maintenance of cardiac function. These FoxO transcription factors control a wide range of crucial cellular processes, including stress resistance, metabolism, cell proliferation, DNA-repair processes, apoptosis and autophagy (Wang, Zhou, & Graves, 2014). They majorly act as transcriptional activators by binding to the consensus binding sequence within the promoters of their target genes (Calnan & Brunet, 2008; Furuyama, Nakazawa, Nakano, & Mori, 2000). The FoxO factors are inhibited by the insulin/insulin-like growth factor signaling, through AKT mediated phosphorylation of the FoxO proteins at three conserved residues, which lead to their nuclear exclusion and suppression of their target gene expression (Tzivion, Dobson, & Ramakrishnan, 2011). Besides phosphorylation, the activity of FoxO is also regulated by other post-translational modifications such as acetylation, methylation and ubiquitination (Wang, Yu, & Huang, 2016).
The effects of FoxO can be beneficial or detrimental during the development of cardiovascular diseases depending upon the nature of stress, cell type and expression levels. FoxO acts as a converging point for multiple signaling pathways known to govern aging and aging-associated changes in the heart. As described in this chapter, the complex network of signaling pathways comprising of insulin/IGF-1 signaling, AMPK, JNK as well as Sirtuins regulate the development of aging-associated cardiovascular dysfunction by modulating the activity of FoxO transcription factors. FoxO plays a critical role in cardiac pathologies associated with aging, such as cardiac hypertrophy, cardiac fibrosis, heart failure, vascular dysfunction, atherosclerosis, hypertension and myocardial ischemia. In addition, FoxO is also implicated in aging-associated metabolic and proteostatic derangements in the heart, which leads to compromised cardiac function. The present chapter will discuss the specific role of different FoxO transcription factors in the development of aging-associated cardiovascular complications along with the relevant mechanisms. The various targets of FoxO transcription factors and the associated processes implicated in the pathogenesis of aging-associated cardiovascular diseases are presented in Fig. 1. In addition, changes observed in the heart of various genetic models of FoxO transcription factors are summarized in Table 1.
Section snippets
Role of FoxO in cardiac remodeling
Age-related changes in the cellular and molecular processes of the cardiomyocytes, fibroblasts and endothelial cells, triggered by biomechanical stresses, cause morphological and structural changes of the heart, which lead to compromised cardiac function (Chiao & Rabinovitch, 2015). Generally, cardiac aging is characterized by left ventricular hypertrophy and fibrosis that contributes to adverse remodeling of heart, eventually leading to heart failure (Steenman & Lande, 2017). Interestingly,
Role of FoxO transcription factors in vascular remodeling and dysfunction
Age-related changes in the structure and function of the vasculature is one of the major cause for the increased prevalence of cardiovascular diseases in older population (Ungvari, Kaley, de Cabo, Sonntag, & Csiszar, 2010). Vascular aging is characterized by increased oxidative stress that occurs due to an imbalance in pro-oxidative and anti-oxidative pathways (Li & Fukagawa, 2010). Further, vascular aging is also associated with increased proliferation and migration of vascular smooth muscle
Role of FoxO in myocardial ischemia and ischemia-reperfusion injury
The myocardial oxygen demand is increased by aging-associated changes in the heart such as left ventricular hypertrophy. Combined with hypertrophy, the coronary atherosclerosis and myocardial microvascular defects increase with age, resulting in increased risk of myocardial ischemia (Paneni et al., 2017). Importantly, restoration of blood flow to the heart following myocardial ischemia, i.e., reperfusion, causes severe oxidative stress and cell death (Murphy & Steenbergen, 2008). In this
Role of FoxO in regulating metabolic homeostasis of heart
Aging-related changes in the heart can induce profound metabolic alterations in the cardiomyocytes. Importantly, failing heart heavily depends on the utilization of glucose for the production of ATP, unlike healthy hearts which predominantly utilize fatty-acids for energy production (Nagoshi, Yoshimura, Rosano, Lopaschuk, & Mochizuki, 2011). It has been shown that the transition from compensatory hypertrophy to heart failure is accompanied by an increase in AKT signaling and reduced FoxO1
Role of FoxO in regulating diet-induced alterations in heart
Calorie-restriction (CR) has been shown to extend organismal lifespan by protecting against age-related diseases, including cardiac dysfunction. However, the timing of the CR during the lifetime of the organism is critical, as CR initiated in 3 month old young mice leads to exacerbated cardiac hypertrophy and fibrosis along with an increased expression of inflammatory and aging-associated markers following CR (Sheng et al., 2017). On the other hand, CR in middle-aged and old mice prevented
Role of FoxO in modulating autophagy and proteasomal degradation
Dysregulation of protein quality control due to defective autophagy or ubiquitin-proteasome system is emerging as a key contributor to the development of aging-related cardiac dysfunction (Ghosh, Vinod, Symons, & Boudina, 2020). FoxO has been shown to regulate both these processes in response to alterations in nutrient availability or stress stimuli. Cardiac specific overexpression of constitutively active FoxO3a has been shown to reduce cardiomyocyte size and decrease heart weight (Schips et
Role of FoxO in regulating age-dependent cardiac functions in flies
Cardiac performance has been shown to decline with aging in different organisms ranging from flies to higher order mammals, including humans (Chiao & Rabinovitch, 2015; Paternostro et al., 2001). In this context, flies with cardiac-specific overexpression of dFOXO or dPTEN which promotes FOXO activity through inhibition of AKT signaling, are shown to be protected against aging-associated decline in heart rate and stress-induced heart failure, suggesting a protective effect of dFOXO against
Conclusion
In summary, FoxO transcription factors regulate a plethora of cellular processes such as stress-response, proliferation, migration, differentiation, apoptosis, autophagy and proteasomal degradation, which play a key role in the development of CVDs. Importantly, the effects of FoxO factors are cell, context and isoform specific and also dose-dependent. Therefore, careful modulation of FoxO activity is essential, while targeting FoxO for treating aging-related cardiovascular diseases.
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