Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds

Brown, David I.; Parry, Traci L.; Willis, Monte S.

doi:10.1002/cphy.c160024

Cited by 9 publications

(10 citation statements)

References 182 publications

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“…Recently, 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 ). Different components of UPS have been egressed out as significant drug targets in the treatment of cancer, immunodeficiencies, and neurodegenerative diseases ( Paul, 2008 ; Shen et al, 2013 ; Pal et al, 2014 ; Upadhyay et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Emergence of Members of TRAF and DUB of Ubiquitin Proteasome System in the Regulation of Hypertrophic Cardiomyopathy

2018

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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.

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Section: Introductionmentioning

confidence: 99%

Emergence of Members of TRAF and DUB of Ubiquitin Proteasome System in the Regulation of Hypertrophic Cardiomyopathy

2018

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“…For that reason, and acknowledging that clinical parameters were continuous variables, correlation analysis was performed, in an effort to uncover associations between UPS elements and markers of AS severity, hypertrophy and RR. Proteasome-based degradation of proteins relies on the serial addition of ubiquitin chains [16]. Thus, the global ubiquitination profile in the LV was studied.…”

Section: Discussionmentioning

confidence: 99%

“…Many ubiquitin ligases have been studied in the heart and reported to regulate cell trophic response [16,17]. Since RR relies heavily on the reversal of hypertrophy, the levels of post-natal muscle-specific ubiquitin ligases, MuRF1, MuRF3 and atrogin-1, were studied.…”

Section: Discussionmentioning

confidence: 99%

“…These are responsible to signal and degrade worn proteins and recycle sarcomeric proteins, the main determinants of cardiac mass [15]. Particularly in what regards to UPS, the activity of E3 ubiquitin ligases is of paramount importance, as these confer substrate-specificity (reviewed in [16,17]). A growing body of evidence shows the relationship between these enzymes and cardiac disease, particularly hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

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Preoperative myocardial expression of E3 ubiquitin ligases in aortic stenosis patients undergoing valve replacement and their association to postoperative hypertrophy

et al. 2020

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Currently, aortic valve replacement is the only treatment capable of relieving left ventricle pressure overload in patients with severe aortic stenosis. It aims to improve cardiac function and revert hypertrophy, by triggering myocardial reverse remodeling. Despite immediately relieving afterload, reverse remodeling turns out to be extremely variable. Among other factors, the extent of reverse remodeling may depend on how well ubiquitin-proteasome system tackle hypertrophy. Therefore, we assessed tagged ubiquitin and ubiquitin ligases in the left ventricle collected from patients undergoing valve replacement and tested their association to the degree of reverse remodeling. Patients were classified according to the regression of left ventricle mass (ΔLVM) and assigned to complete (ΔLVM�15%) or incomplete (ΔLVM�5%) reverse remodeling groups. No direct inter-group differences were observed. Nevertheless, correlation analysis supports a fundamental role of the ubiquitinproteasome system during reverse remodeling. Indeed, total protein ubiquitination was associated to hypertrophic indexes such as interventricular septal thickness (r = 0.55, p = 0.03) and posterior wall thickness (r = 0.65, p = 0.009). No significant correlations were observed for Muscle Ring Finger 3. Surprisingly, though, higher levels of atrogin-1 were associated to postoperative interventricular septal thickness (r = 0.71, p = 0.005). In turn, Muscle Ring Finger 1 correlated negatively with this postoperative hypertrophy marker (r =-0.68, p = 0.005), suggesting a cardioprotective role during reverse remodeling. No significant correlations were found with left ventricle mass regression, although a trend for a negative association between the ligase Murine Double Minute 2 and mass regression (r =-0.44, p = 0.10) was found. Animal studies will be necessary to understand whether this ligase is protective or detrimental. Herein, we show, for the first time, an association between the preoperative myocardial levels of ubiquitin ligases and postoperative hypertrophy, highlighting the therapeutic potential of targeting ubiquitin ligases in incomplete reverse remodeling.

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“…The adult heart endures a wide range of physiological and pathophysiological stresses during life. Accumulating evidence indicates that ubiquitylation is involved in developing cardiac diseases [ 17 , 56 , 57 , 58 , 59 , 60 ]. Cardiac proteins are in a dynamic state of continual degradation and resynthesis and are thought to replace all in 30 days under normal circumstances.…”

Section: Importance Of Ubiquitylation In Cardiac Diseasementioning

confidence: 99%

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

Goto

Otaki

Watanabe

et al. 2021

IJMS

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Despite advances in medicine, cardiac disease remains an increasing health problem associated with a high mortality rate. Maladaptive cardiac remodeling, such as cardiac hypertrophy and fibrosis, is a risk factor for heart failure; therefore, it is critical to identify new therapeutic targets. Failing heart is reported to be associated with hyper-ubiquitylation and impairment of the ubiquitin–proteasome system, indicating an importance of ubiquitylation in the development of cardiac disease. Ubiquitylation is a post-translational modification that plays a pivotal role in protein function and degradation. In 1995, homologous to E6AP C-terminus (HECT) type E3 ligases were discovered. E3 ligases are key enzymes in ubiquitylation and are classified into three families: really interesting new genes (RING), HECT, and RING-between-RINGs (RBRs). Moreover, 28 HECT-type E3 ligases have been identified in human beings. It is well conserved in evolution and is characterized by the direct attachment of ubiquitin to substrates. HECT-type E3 ligase is reported to be involved in a wide range of human diseases and health. The role of HECT-type E3 ligases in the development of cardiac diseases has been uncovered in the last decade. There are only a few review articles summarizing recent advancements regarding HECT-type E3 ligase in the field of cardiac disease. This study focused on cardiac remodeling and described the role of HECT-type E3 ligases in the development of cardiac disease. Moreover, this study revealed that the current knowledge could be exploited for the development of new clinical therapies.

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Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds

Cited by 9 publications

References 182 publications

Emergence of Members of TRAF and DUB of Ubiquitin Proteasome System in the Regulation of Hypertrophic Cardiomyopathy

Emergence of Members of TRAF and DUB of Ubiquitin Proteasome System in the Regulation of Hypertrophic Cardiomyopathy

Preoperative myocardial expression of E3 ubiquitin ligases in aortic stenosis patients undergoing valve replacement and their association to postoperative hypertrophy

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

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