Abstract
The ubiquitin proteasome system (UPS) plays an imperative role in many critical cellular processes, frequently by mediating the selective degradation of misfolded and damaged proteins and also by playing a non-degradative role especially important as in many signaling pathways. Over the last three decades, accumulated evidence indicated that UPS proteins are primal modulators of cell cycle progression, DNA replication, and repair, transcription, immune responses, and apoptosis. Comparatively, latest studies have demonstrated a substantial complexity by the UPS regulation in the heart. In addition, various UPS proteins especially ubiquitin ligases and proteasome have been identified to play a significant role in the cardiac development and dynamic physiology of cardiac pathologies such as ischemia/reperfusion injury, hypertrophy, and heart failure. However, our understanding of the contribution of UPS dysfunction in the plausible development of cardiac pathophysiology and the complete list of UPS proteins regulating these afflictions is still in infancy. The recent emergence of the roles of TNF receptor-associated factor (TRAFs) and deubiquitinating enzymes (DUBs) superfamily in hypertrophic cardiomyopathy has enhanced our knowledge. In this review, we have mainly compiled the TRAF superfamily of E3 ligases and few DUBs proteins with other well-documented E3 ligases such as MDM2, MuRF-1, Atrogin-I, and TRIM 32 that are specific to myocardial hypertrophy. In this review, we also aim to highlight their expression profile following physiological and pathological stimulation leading to the onset of hypertrophic phenotype in the heart that can serve as biomarkers and the opportunity for the development of novel therapies.
Highlights
Cardiac hypertrophy is the second most common type of heart disease and has an incidence of 1 in 500 people worldwide (Jacoby et al, 2013)
Numerous signaling pathways are believed to be involved in leading toward hypertrophy for example, signals from hormones like insulin, thyroid and other mechanical forces leading to the activation of insulin-like growth factor-I (IGF-I)–phosphatidylinositol 3-kinase (PI3K)–Akt/protein kinase B (PKB) signaling, mammalian target of rapamycin pathway, calcineurin–nuclear factor of activated T cells (NFAT) pathway, mitogen-activated protein kinase (MAPK), tumor necrotic factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) (Lips et al, 2003; Wilkins and Molkentin, 2004; Dorn and Force, 2005; Heineke and Molkentin, 2006; Gupta et al, 2007)
Much is known about the pathways that regulate hypertrophic responses, the regulatory proteins that can be targeted to avert the development of heart failure resulting from cardiac hypertrophy are poorly defined
Summary
Cardiac hypertrophy is the second most common type of heart disease and has an incidence of 1 in 500 people worldwide (Jacoby et al, 2013). UPS is known to significantly influence the maintenance of a balance of cardiac proteins both at steady state and in case of any type of stress (Beardslee et al, 1998) This balance is achieved by the continuous degradation and synthesis of the structural proteins such as sarcomere and proteins involved in the regulation of different signaling pathways (Eble et al, 1999). For instance, an adenoviral overexpression of Atrogin-1 and MuRF1 E3 ligases suppresses the cardiac hypertrophy induced by phenylephrine treatment (Wertz et al, 2004; Maejima et al, 2014) These studies will provide novel insight into the E3s and DUBs operated signaling cascades and their distinct role in cardiac myopathies (Parry and Willis, 2016; Brown et al, 2017). We have highlighted the role of the different E3 ligases and DUBs in regulating cardiac hypertrophy via different signaling cascades, further adding to the list as potential drug targets to attenuate or prevent the onset of cardiac hypertrophy
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