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The role of deubiquitinases in cardiac disease

Published online by Cambridge University Press:  25 March 2024

Xiaona Zhan
Affiliation:
Department of Nephrology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Yi Yang
Affiliation:
Department of Nephrology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Qing Li*
Affiliation:
Department of Nephrology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Fan He*
Affiliation:
Department of Nephrology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
*
Corresponding authors: Qing Li; Email: qing.li@tjh.tjmu.edu.cn, Fan He; Email: fhe@tjh.tjmu.edu.cn
Corresponding authors: Qing Li; Email: qing.li@tjh.tjmu.edu.cn, Fan He; Email: fhe@tjh.tjmu.edu.cn
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Abstract

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Type
Review
Creative Commons
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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
Copyright © The Author(s), 2024. Published by Cambridge University Press

Introduction

Protein synthesis and degradation must be in balance for cellular proteins to remain stable (Ref. Reference Powers1). The ubiquitin-proteasome system primarily controls the majority of protein degradation in eukaryotic cells (Ref. Reference Fulda, Rajalingam and Dikic2). Ubiquitin is a polypeptide composed of 76 highly conserved amino acids (Ref. Reference Kolla3). Ubiquitination is the process of connecting ubiquitin with protein to form the ubiquitin chains under the action of ubiquitin ligase. Ubiquitination regulates a variety of biological functions, the most important of which is protein degradation mediated by 26S proteasome (Ref. Reference Yau and Rape4). Ubiquitination is a reversible process, which is strictly regulated. Deubiquitination is the main negative regulation process. It recognizes and cleaves the ubiquitin chains of substrate protein through a series of deubiquitinases, thus inhibiting the degradation process of protein (Ref. Reference Mevissen and Komander5). The balance between ubiquitination and deubiquitination is crucial in the human body, regulating a variety of diseases such as cancers (Ref. Reference Sun, Liu and Yang6), neurodegenerative diseases (Ref. Reference Bello7) and regulating immune cells (Ref. Reference Zhu8).

Recently, more and more research has confirmed that deubiquitinases represent a pivotal regulator in cardiac disease by recognizing different substrate proteins and regulating a variety of signalling pathways and mechanisms (Refs Reference Bi9, Reference Zhang10). However, until now, there are few reviews on the regulatory role of deubiquitinases in cardiac disease. This review summarizes the recent basic research on the function of deubiquitinases in cardiac disease, specifically introduces the emerging roles of deubiquitinases in regulating cardiac diseases and their specific molecular mechanism, and provides a new strategy for the therapy of cardiac disease in the future.

Ubiquitin proteasome system

Since it was initially identified in the 1970s, ubiquitin has been found in a wide variety of creatures (Ref. Reference Hershko and Ciechanover11). Ubiquitin activating enzyme (E1) joins the lysine residue at the C-terminal of ubiquitin to its own cysteine residue during the ubiquitination process by hydrolysing ATP. After the ubiquitin has been delivered to ubiquitin coupling enzyme (E2), the target protein is then joined with ubiquitin by the ubiquitin ligase (E3) (Ref. Reference Salas-Lloret and Gonzalez-Prieto12). The majority of proteins in the human body can be marked with ubiquitin, and the 26S proteasome can identify and degrade ubiquitinated proteins. There are many different forms of ubiquitination, but the three most prevalent types are monoubiquitination, K48-linked and K63-linked polyubiquitination (Ref. Reference Martinez-Ferriz13). After the substrate protein is modified by ubiquitination, different types of ubiquitination will lead to different protein fate. Monoubiquitination is associated with protein recognition or allosteric regulation, while K48-linked and K63-linked polyubiquitination may lead to protein degradation and signal transduction, respectively (Ref. Reference Mevissen and Komander5).

As one of the most important post-translational modifications, ubiquitination not only plays an important role in regulating protein degradation, but also plays a key role in regulating cell cycle (Ref. Reference Dang, Nie and Wei14), antigen presentation (Ref. Reference Loureiro and Ploegh15), immune signal transduction (Ref. Reference Ebner, Versteeg and Ikeda16), transcription regulation and apoptosis (Ref. Reference Cockram17).

Deubiquitinases

Deubiquitination refers to the process of recognizing ubiquitin-labelled proteins, hydrolysing and removing ubiquitin chains on some amino acid residues of substrate proteins under the action of a series of deubiquitinases (Ref. Reference Harrigan18). Deubiquitinases stabilize proteins to maintain their functions by reversing the ubiquitination process. Deubiquitinases can be divided into six families: the ubiquitin-specific proteases (USPs), the ovarian tumour-related proteases (OTUs), the ubiquitin C-terminal hydrolases (UCHs), Machado Joseph disease proteins (MJDs), Mindys family motif interacting with ubiquitin containing novel dub family (MINDYs) and JAB1/MPN/MOV34 metalloproteinases (JAMMs). The first five deubiquitinases belong to cysteine protease (Ref. Reference Lange, Armstrong and Kulathu19). The USPs family is the family with the most members in the deubiquitinases, which can recognize the ubiquitin chains linked by K48, K63 and MET1. The protease of the MJD family tends to recognize the K48-linked and K63-linked polyubiquitination, the protease of JAMMs tends to recognize the K63-linked polyubiquitination, and MINDYs tend to recognize and hydrolyse the K48-linked polyubiquitination from the distal end (Ref. Reference Mevissen and Komander5).

Deubiquitinases may either deubiquitinate a broad area surrounding the hydrophobic region of ubiquitin or they can precisely remove ubiquitin by identifying and hydrolysing the ester bond, peptide bond or isopeptide bond at the carboxyl terminus of ubiquitin (Ref. Reference Lange, Armstrong and Kulathu19). Deubiquitinases can also inhibit the function of E3 ligase by hydrolysing the peptide linkage that connects the target protein's lysine residue to the C-terminal of ubiquitin (Ref. Reference Komander, Clague and Urbe20). Deubiquitinases vary in number depending on the species, and there are roughly 100 different types in human cells (Ref. Reference Clague21). Numerous studies have demonstrated that deubiquitinases can regulate cell growth and development, mediate physiological signalling pathways and maintain cell homeostasis (Ref. Reference Wertz and Murray22). Moreover, deubiquitinases also exert a significant regulatory influence over the pathophysiological processes of a number of diseases, including tumours (Ref. Reference Young23), inflammatory bowel disease (Ref. Reference Chen24) and vascular disease (Ref. Reference Wang25).

Deubiquitinase is an essential regulator of cardiac physiology and homeostasis

USP17 subfamily is comprised of USP17k, USP17l, USP17m and USP17n. Researchers discovered that the USP17 subfamily members were significantly expressed in human myocardial tissue, indicating that the USP17 family may be crucial in preserving the physiological function of the heart (Ref. Reference Shin26). Additionally, DUB-1a, a newly discovered deubiquitinase subfamily member, was discovered in lymphocytes for the first time. Researchers provided experimental evidence that DUB-1a was also expressed in the mouse heart, suggesting that it may be involved in preserving cardiac homeostasis (Ref. Reference Baek27).

A critical role of cylindromatosis (CYLD) in maintaining subcellular region was supported by research in which CYLD promoted the stability of plakoglobin by reducing its K63-linked ubiquitin chains. Plakoglobin is an intermediate protein that stabilizes the gap junction of myocardial cells. The deubiquitination of plakoglobin stabilized its connection with desmoplakin, contributing to the transmission of Cx43 to the inserted intervertebral disc. The stable existence of CYLD is crucial for the development and maturation of myocardial cells (Ref. Reference Xie28).

Role of deubiquitinases in cardiac disease

Cardiac hypertrophy

The protein kinase pathway (PI3K/Akt signalling pathway, cGMP/PKG signalling pathway, etc.), calcium-mediated signalling pathway (CaMKⅡ signalling pathway, CaN-NFAT signalling pathway, etc.) and Wnt signalling pathway are the main signalling pathways currently involved in pathological myocardial hypertrophy (Refs Reference Zhu29, Reference Nakamura and Sadoshima30). Numerous studies have shown that deubiquitinases modulate the development of cardiac hypertrophy by regulating different signalling pathways that are associated with cell inflammation (Ref. Reference Bacmeister31), apoptosis (Ref. Reference Hu32), autophagy (Ref. Reference Shi and Jiang33), mitochondrial homeostasis (Ref. Reference Yang34) and metabolic changes (Ref. Reference Gibb and Hill35) (Fig. 1).

Figure 1. The main deubiquitinases involved in the pathogenesis of cardiac hypertrophy. Notes: Multiple deubiquitinases regulate cardiac hypertrophy through mechanisms such as autophagy, ROS, RNA methylation, signal transduction, and calcium homeostasis. CYLD: cylindromatosis; mTOR: mammalian target of rapamycin; Rab7: Ras-related protein Rab-7a; Erk: extracellular signal-regulated kinase; Nrf2: nuclear factor erythroid-2-related factor 2; USP: ubiquitin-specific protease; METTL3: metallothionein-like 3; GSK3β: Glycogen synthase kinase 3β; UCHL1: ubiquitin C-terminal hydrolases L1; EGFR: epidermal growth factor receptor; HIF-1α: hypoxia inducible factor-1α; TAK1: transforming growth factor-β-activated kinase 1; JNK1/2: c-Jun N-terminal kinase 1/2; SIRT6: sirtuin 6; AKT: protein kinase B; JOSD2: josephin domain-containing protein 2; SERCA2a: sarco/endoplasmic reticulum Ca2+-ATPase.

Previous studies have found that the expression profile of USP has changed in hypertrophic hearts, which indicated that USP may be a biomarker of cardiac hypertrophy or a regulator in the progression of cardiac remodelling. In the chronic heart failure model, the mRNA expression of USP19 was significantly downregulated in chronic heart failure models (Ref. Reference Klaeske36). In addition, by comparing the GEO dataset and the mRNA level of USP2 in hypertrophic heart induced by trans-arterial coarctation (TAC), it was determined that the expression of USP2 was downregulated in hypertrophic heart, and the overexpression of USP2 could relieve the cardiac hypertrophy induced by TAC. However, further research was still warranted to explore the molecular mechanism of USP2 in myocardial hypertrophy caused by pressure overload (Ref. Reference Xing37).

Transforming growth factor-activated kinase 1 (TAK1) is a MEKK family member and the upstream of JNK1/2 and p38 (Refs Reference Mukhopadhyay and Lee38, Reference Li39). Overexpression of TAK1 could promote the activation of NF-κB and NFAT signalling pathways, and upregulate the expression of cardiac hypertrophy markers (Ref. Reference Li40). In the hearts of patients with heart failure and hypertrophic rodent hearts, the mRNA and protein expression of USP4 was downregulated, while overexpression of USP4 could alleviate cardiac hypertrophy both in vivo and in vitro. USP4 played an anti-myocardial hypertrophy effect in regulating pathological myocardial hypertrophy and fibrosis by blocking the activation of the TAK1-(JNK1/2)/p38 signalling pathway (Ref. Reference He41). However, unlike the anti-hypertrophic effect of USP4, USP22 exerted its pro myocardial hypertrophy effect by activating the TAK1 signalling pathway. USP22 stabilized the hypoxia-inducible factor-1α (HIF-1α) protein through its deubiquitinase activity, activating the TAK1 signalling pathway and exacerbating myocardial hypertrophy-induced pressure overload (Ref. Reference Jiang42).

GSK-3β, as a widely expressed serine threonine protein kinase, can phosphorylate different substrates and act as a significant negative regulator in regulating cardiac development and myocardial hypertrophy by activating a wide range of downstream signalling molecules (Ref. Reference Zhao43). In a variety of rodent models of cardiac hypertrophy, the specific overexpression of GSK-3β in myocardium could significantly alleviate myocardial hypertrophy and fibrosis by reducing the nuclear localization of NFAT (Refs Reference Tariq, Uppulapu and Banerjee44, Reference Antos45). The phosphorylation of GSK-3β is bidirectional. The phosphorylation of the C-terminal Tyr216 site can activate GSK-3β (Ref. Reference Duda46), while the phosphorylation of C-terminal Ser389 and Thr390 sites leads to the inactivation of GSK-3β (Ref. Reference Thornton47). USP14 has been shown to upregulate the phosphorylation of GSK-3β. In the models of myocardial hypertrophy induced by abdominal aortic constriction (AAC) and Ang II, USP14 accelerated the development of cardiac hypertrophy and worsen cardiac function by activating GSK-3β. However, it is not clear whether USP14 directly combined with GSK-3β, or indirectly interacted with GSK-3β through other molecules. Further experimental research is needed to investigate the interaction between USP14 and GSK-3β and the phosphorylation site of GSK-3β (Ref. Reference Liu48).

In addition to the typical signalling pathways, skeletal muscle LIM protein 1 (SLIM1) is a key factor related to the pathogenesis of myopathy and cardiomyopathy (Refs Reference Yang49, Reference McGrath50). A study on USP15 transgenic mice showed that the upregulation of USP15 exacerbated myocardial hypertrophy by interacting with the SLIM1 protein, cutting the SLIM1 ubiquitin chains and stabilizing the SLIM1 protein. Additionally, in the cardiac tissue of USP15 transgenic mice, the mRNA level of SLIM1 was also higher than that of WT mice, which indicated that USP15 may upregulate the expression of SLIM1 both at the transcriptional level and post-translational modification level (Ref. Reference Isumi51).

The calcium homeostasis of cardiomyocyte is indispensable for the maintenance of cardiac function (Refs Reference Zhihao52, Reference Sitsel53). Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), located on the sarcoplasmic reticulum, is regarded as a key protein for maintaining calcium homeostasis, and multiple studies have shown that there are several post translational modification sites in SERCA2a (Ref. Reference Stammers54). Research showed that USP25, as a protective protein of the heart, played an anti-hypertrophic role in pathological myocardial hypertrophy (Ref. Reference Ye55). Ye et al. found that knocking out USP25 in mice exacerbated myocardial hypertrophy induced by angiotensin II and TAC. USP25 exerted its anti-hypertrophic effect by regulating the SERCA2a. USP25 stabilized intracellular calcium homeostasis and alleviated myocardial hypertrophy by removing the K48-linked ubiquitin chains of SERCA2a protein (Ref. Reference Ye55). Coincidentally, the team also found that JOSD2 maintained myocardial calcium homeostasis by upregulating SERCA2a, thereby attenuating cardiac hypertrophy (Ref. Reference Han56). However, there are currently no agonists or analogues for USP25 or JOSD2, and more research is needed to promote their clinical conversion.

The sirtuin protein family (SIRT family), a highly conserved protein, is a kind of nicotinamide adenine dinucleotide (NAD+) dependent deacetylase. Among the SIRT family members, SIRT6 has been proved in multiple studies to regulate the NF-κB signalling pathway or the Akt signalling pathway, both of which were connected to the development of cardiac hypertrophy (Ref. Reference Guo57). Zhang et al. proved that USP10 exerted its anti-hypertrophic effect mainly by inhibiting the Akt signalling pathway, rather than through the common downstream signalling pathways of USP10 (such as p53, AMPK, TRAF6). Further studies showed that SIRT6 acted as an intermediate messenger of USP10 inhibiting the Akt signalling pathway. USP10 bound and stabilized SIRT6 by inhibiting the activation of Akt/GSK3β and mTOR/p70S6k signalling pathway, resulting in the remission of myocardial hypertrophy and fibrosis (Ref. Reference Zhang10). Aside from SIRT6, SIRT2 also contributes to the occurrence and progression of cardiac hypertrophy. SIRT2-deficient mice develop spontaneous pathological cardiac hypertrophy through LKB1/AMPK (Ref. Reference Tang58). Mei et al. discovered that the mRNA and protein level of CSN6 was upregulated both in the Ang II-induced hypertrophic cardiomyocyte and hypertrophic cardiac tissue. The researchers pointed out that inhibiting the expression of CSN6 might relieve the progression of cardiac hypertrophy. Additional research revealed that CSN6 could contribute to cardiac hypertrophy by stabilizing Nkx2 and removing the K48-linked ubiquitin chains of Nkx2.2. Nkx2.2, a common transcription factor, attached to the promoter of SIRT2 and prevented the activation of transcription. CSN6 stabilized Nkx2.2, which blocked the transcription of SIRT2, resulting in ventricular hypertrophy and heart failure (Ref. Reference Mei59).

Signal transducer and activator of transcription 3 (STAT3) is a protein that is involved in both cytoplasmic signal transduction and nuclear transcriptional activation. It is one of the key factors exacerbating myocardial hypertrophy and is regulated by deubiquitinase. Wang et al. demonstrated that OTUD1 promoted the development of pathological myocardial hypertrophy by removing the K63-linked ubiquitin chains of STAT3 and stabilizing the protein in various rodent models of myocardial hypertrophy. This study further elucidated that OTUD1 bound to the SH2 domain of STAT3 through its cysteine site at position 320, thereby exerting the effect of deubiquitination (Ref. Reference Wang60).

In addition to transcription factors, at the level of gene regulation, methyltransferases in cardiomyocytes are also indirectly regulated by deubiquitinases. USP12 deubiquitinated p300 to activate the transcription of methyltransferase-like 3 (METTL3), which resulted in the abnormal m6A RNA methylation in cardiomyocyte and exacerbated cardiac hypertrophy (Ref. Reference Lu61).

Even though the function of autophagy in the heart is still debatable, recent studies tend to view the activation of autophagy as a protective process of cardiac hypertrophy (Ref. Reference Miyamoto62). Autophagy is regulated by several kinds of deubiquitinases, including CYLD (Refs Reference Colombo63, Reference Liu64, Reference Ming65). An experiment has demonstrated that CYLD could give rise to cardiac hypertrophy by mediating autophagy in cardiac hypertrophy induced by pressure overload. Specifically, compared with wild-type mice with TAC-induced cardiac hypertrophy, autophagic flow in cardiac myocytes was significantly blocked in the hypertrophic heart of mice with cardiomyocyte-specific CYLD overexpression, resulting in cardiac morphological changes and dysfunction in transgenic mice (Ref. Reference Qi66). The role of CYLD was only related to the restricted autolysosome efflux but did not affect basic autophagy and the combination of autophagosome and lysosome. Further study on the downstream molecules of CYLD revealed that the hypertrophic effect of CYLD was partly attributed to the inactivation of mTORC1 and the upregulation of Rab7, which was important in the excretion of autolysates. Another study provided another potential molecular mechanism of CYLD in pressure load-induced cardiac hypertrophy. CYLD blocked Nrf2-mediated antioxidant capacity by inhibiting Erk, p38/AP-1 and c-Myc pathways, thereby promoting oxidative stress in myocardial tissue and aggravating myocardial hypertrophy and ventricular remodelling (Ref. Reference Wang67).

Epidermal growth factor receptor (EGFR) is a member of receptor tyrosine kinase whose deficiency could worsen myocardial hypertrophy, cardiac dysfunction and arterial hypotension (Refs Reference Guo68, Reference Schreier69). A series of classic pro-hypertrophic factors, such as Ang II and norepinephrine, could bind to their cell membrane receptors and activate EGFR (Refs Reference Peng70, Reference Xie71). The intracellular tyrosine kinase domain of EGFR actively participates in signal transduction, activating the PI3K/Akt, MAPK and other signalling pathways. In addition, patients receiving EGFR tyrosine kinase treatment are particularly prone to cardiac complications (Ref. Reference Hnatiuk72). Li et al. identified UCHL1 as a pathogenic factor of cardiac hypertrophy through microarray analysis. By recognizing and cutting the ubiquitin chains connected with EGFR, UCHL1 reduced the degradation of EGFR through the ubiquitin-proteasome system, thus continuously activating EGFR, Akt and ERK signalling pathways, leading to myocardial hypertrophy (Ref. Reference Bi9). The cardiac dysfunction of mice with cardiac hypertrophy induced by TAC was dramatically relieved after treatment with LDN-57444, an inhibitor of UCHL1, indicating that UCHL1 may be employed as a potential drug target for the therapy of cardiac hypertrophy in the future.

Moreover, another study on the role and mechanism of UCHL1 in cardiac hypertrophy induced by pressure overload revealed that the expression of UCHL1 was upregulated in hypertrophic heart, while the overexpression of UCHL1 could inhibit the growth of fibroblasts, and the inhibition of growth was not related to apoptosis. Interestingly, other research has unveiled that UCHL1 could enhance the proliferation of a range of cells, such as HeLa cells, Neuro2a cells, human cancer cell lines h727 and MCF (Ref. Reference Kabuta73). Based on the conclusion of the above research, investigators confirmed that the inhibitory effect of UCHL1 on cell growth inhibition is unique to cardiac fibroblasts. The inhibitory effect was caused by affecting the level of cyclin-dependent kinase inhibitor protein p21WAF1/Cip1 instead of affecting the signal pathway related to fibroblast proliferation. Interestingly, further experiments of the team showed that UCHL1 increased the protein content of p21WAF1/Cip1 by inhibiting the autophagy lysosomal degradation of p21 rather than by inhibiting the ubiquitin-proteasome system (Ref. Reference Zhang74).

Deubiquitinases also exert regulatory effects on the pathogenesis of heart failure-related stroke. Researchers analysed and compared heart failure-related chip data and stroke-related chip data through bioinformatics analysis. OTU deubiquitinase with linear linkage specificity (OTULIN) was identified as a regulator in the pathogenesis of heart failure-related stroke through the intersection analysis of heart failure-related chip data and stroke-related chip data. It may participate in the regulation of heart failure-related stroke by participating in protein ubiquitination and Wnt signalling. OTULIN is expected to become a key regulator in the pathophysiological process of heart failure-related stroke (Ref. Reference Liu75).

Deubiquitinases are also involved in the pathogenesis of right ventricular hypertrophy (RVH). The researchers indicated that the expression of UCHL1 was evaluated in the RVH model induced by pulmonary artery ligation (PAC). However, whether UCHL1 is involved in the pathogenesis of RVH and its molecular mechanism is not yet clear, and additional research is warranted to clarify the role of UCHL1 in RVH (Ref. Reference Rajagopalan76).

Myocardial infarction (MI) and myocardial ischaemia reperfusion (I/R) injury

MI is driven by the imbalance between myocardial oxygen supply and demand, which results in myocardial necrosis. Researchers discovered that the mRNA expression of USP19 was downregulated in the acute model of MI, which raised the possibility that USP19 could have a special function in MI (Ref. Reference Klaeske36). However, the mechanism of USP19 in MI remains unknown.

Apoptosis is a key process in the pathogenesis of MI and cardiac dysfunction. ABRO1 is also one of the four subunits (ABRO1, NBA1, BRE and BRCC36 proteins) of deubiquitinase BRISC. According to the research, the hearts of MI patients were characterized by higher protein levels of ABRO1 protein. The protein level ABRO1 was upregulated in the heart of MI mice and the knockdown of ABRO1 worsened myocardial cell apoptosis. However, it is unclear how ABRO1 specifically prevents cardiomyocytes from cell apoptosis (Ref. Reference Cilenti77). Besides, study has shown that the expression of USP7 was upregulated in H9C2 cardiomyocytes cultured under hypoxia and in the heart of MI rats, and overexpression of USP7-induced inflammation and apoptosis of cardiomyocytes, leading to aggravation of MI injury. The study further pointed out that the upregulation of USP7 in the MI model was partly due to the downregulation of miR-409-5p (Ref. Reference Xue78). Other researchers detected the expression of USP6 and USP47 from monocytes isolated from peripheral blood samples of MI patients and healthy controls. The expression of USP6 and USP47 was upregulated, especially the level of USP47. The team further found that USP47 may enhance the activity of the NF-κB promoter, activating the NK-κB pathway, thereby promoting cardiomyocyte apoptosis and I/R injury (Ref. Reference Hu79).

Ferroptosis is a kind of programmed cell death that depends on iron, which is different from apoptosis and necrosis. Inhibition of ferroptosis can effectively reduce myocardial injury caused by ischaemia-reperfusion (Ref. Reference Zhao80). The expression of USP7 was evaluated in the myocardial tissue of rats with ischaemia-reperfusion injury. Knockdown of USP7 could inhibit ferroptosis by deubiquitinased p53. The deficiency of USP7 reduced MI area and alleviated myocardial fibrosis through the inhibition of p53/TfR1 pathway (Ref. Reference Tang81). In addition to the deubiquitinase mentioned above, recent study has shown that OTUD5 played an important role in the mechanism of ferroptosis exacerbating myocardial ischaemia-reperfusion injury. OTUD5 inhibited ferroptosis and alleviated myocardial injury by directly binding to glutathione peroxidase 4 (GPX4), the key protein of ferroptosis, and removing the K48-linked ubiquitin chains of GPX4 (Ref. Reference Liu82).

Deubiquitinase can not only regulate myocardial cell apoptosis and ferroptosis, but also modulate myocardial cell pyroptosis. Recent study has shown that USP11 promoted cardiomyocyte pyroptosis and exacerbated myocardial ischaemia-reperfusion injury by binding to TRAF3 protein and hydrolysing its ubiquitin chains (Ref. Reference Zhang83).

In addition to the programmed cell death, inflammatory cells and inflammatory factors are also important mechanisms for the occurrence and development of MI. As a cytokine combined with ST2, IL-33 plays a protective role in acute MI by reducing inflammation and apoptosis. It was reported that USP17 maintained the stability of IL-33 by cleaving and hydrolysing both the K48- and K63-linked ubiquitin chains (Ref. Reference Ni84). In the heart of AMI mice, inhibition of lncRNA ANRIL weakened the degradation of IL-33 mediated by USP17. Reduction of degradation of IIL33 through the ubiquitin proteasome system alleviates cardiac dysfunction and cardiac fibrosis by reducing infarct size and inhibits cell apoptosis (Ref. Reference Yang85).

Previous studies have shown that dual specificity phosphatase 1 (DUSP1)-mediated JNK dephosphorylation participated in protecting the heart from ischaemia-reperfusion injury through the anti-apoptotic effect (Ref. Reference Jin86). According to recent research, USP49 has been confirmed as a regulator of DUSP1-JNK1/2 signal transductions. The expression of USP49 was upregulated in the I/R injury model on AC16 cardiomyocytes, and the signal transduction pathway of DUSP1-JNK1/2 was activated to exert its anti-apoptotic role (Ref. Reference Zhang87).

After myocardial ischaemia-reperfusion injury, myocardial cell apoptosis, autophagy and immune cell infiltration prompt the imbalance of a series of cytokines, eventually activating cardiac fibroblasts and leading to myocardial fibrosis (Ref. Reference Travers88). TGFβ/Smad4 signalling pathway is identified as a classic pro-fibrosis pathway and is modulated by USP10 (Ref. Reference Hanna and Frangogiannis89). It is demonstrated that, in fibroblasts, HSP47 aggravated chronic fibrosis after myocardial ischaemia-reperfusion by recruiting USP10, which removed the ubiquitin chains of Smad4, and stabilized Smad4 protein (Ref. Reference Xie90).

In addition, under pathological conditions such as the stimulation of TGF-β, myocardial fibroblasts undergo glycometabolic reprogramming, mainly manifested as enhanced glycolysis (Refs Reference Zhao91, Reference Chen92, Reference Ji93). Inhibiting glycolysis could alleviate myocardial fibrosis. Researchers found that the protein level of PFKFB3, a sort of glycolytic enzyme, was upregulated by the deubiquitinase OTUD4 in myocardial fibroblasts of post MI mice. OTUD4 promoted the stability of PFKFB3, leading to enhanced glycolysis and exacerbating cardiac fibrosis (Ref. Reference Wang94).

Based on previous studies, sevoflurane postconditioning has been considered as a potential treatment to protect the myocardium from I/R injury by limiting the size of MI, reversing myocardial dysfunction, and improving blood circulation (Ref. Reference Benoit95). Researchers found that the expression of USP22 was upregulated in the hearts of I/R mice treated with sevoflurane postconditioning, and knockdown of USP22 could reverse the protective effect of sevoflurane. Sevoflurane postconditioning upregulated USP22, which increased the protein content of lysine-specific demethylase 3A (KDM3a) in the promoter region of YAP1 by cutting the ubiquitin chains of the protein. The upregulation of USP22 indirectly promoted the transcription of YAP1, thereby reduced myocardial cell injury (Ref. Reference Song96).

Besides, appropriate level of autophagy in cardiomyocytes is considered as a protective mechanism determining the cardiac remodelling. Excessive activation or inhibition of autophagy could deteriorate MI (Refs Reference Wang97, Reference Liu98). Research has shown that deficiency of UCHL1 in the myocardium after MI could exacerbate cardiac remodelling by inhibiting autophagy and decreasing autophagic flux. The research further revealed that the upregulation of autophagic flux was induced by the abnormal formation of autophagosome instead of the increased degradation of autophagosomes. Interestingly, this research pointed out that the absence of UCHL1 in cardiomyocytes has little impact on heart development. No abnormalities were observed in the cardiac development of UCHL1-specific knockout mice before 14 weeks of age (Ref. Reference Wu99) (Fig. 2).

Figure 2. The main deubiquitinases involved in the development of myocardial infarction. Notes: A series of deubiquitinases regulate myocardial infarction through apoptosis, ferroptosis, pyroptosis or metabolic reprogramming. USP: ubiquitin-specific protease; TRAF3: TNF receptor-associated factor 3; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; OTUD: ovarian tumor-related deubiquitinase; NF-κB: nuclear factor kappa-B; TfR1: transferrin receptor 1; GPX4: glutathione peroxidase 4; DUSP1: dual specificity phosphatase 1; JNK1/2: c-Jun N-terminal kinase 1/2; UCHL1: ubiquitin C-terminal hydrolases L1.

Diabetes mellitus (DM) related cardiac disease

Diabetic heart disease is characterized by dysregulated cardiac structure and function that is independent of diabetic macrovascular complications (including hypertension, coronary artery disease and atherosclerosis) (Ref. Reference Ritchie and Abel100). Mitochondria are important integrators of redox signal and metabolic flux, and mitochondria dysfunction is involved in the occurrence and development of diabetic heart disease (Ref. Reference Dillmann101). S-sulfhydrylation is a new post-translational modification of specific cysteine residues on target proteins by H2S (Ref. Reference Gupta102). A study has shown that under the conditions of high glucose and high fat in vivo and in vitro, the S-sulfhydrylation of USP8 was significantly reduced, while after exogenous H2S treatment, the S-sulfhydrylation level of USP8 was increased, promoting the combination of USP8 and Parkin. The combination of USP8 and Parkin ameliorated cardiac dysfunction in mice with type2 diabetes mellitus (T2DM) by regulating mitochondrial autophagy, reducing mitochondrial fusion and improving cell mitochondrial function (Ref. Reference Sun103). The deubiquitinase-regulated downstream process involved not only mitochondrial autophagy, but also the abundance alterations of transcription factors. Y-box binding protein-1 (YB-1), as a regulatory factor for transcription and translation, protects cardiomyocytes from apoptosis and ameliorates cardiac fibrosis (Ref. Reference Choong104). YB-1 is regulated by various post-translational modifications, including ubiquitination (Ref. Reference Yin105). Study in vitro and in vivo indicated that hyperglycaemia caused the phosphorylation of S102 site of YB-1 in cardiomyocytes, which weakened the interaction between YB-1 and OTUB1, thus promoting the degradation of YB-1 through ubiquitin-proteasome pathway, leading to aggravation of diabetes cardiomyopathy (Ref. Reference Zhong106).

Compared with the general population, patients with T2DM are more likely to suffer from MI, which is a multi-step event characterized by myocardial fibrosis, cardiomyocyte apoptosis and cardiac dysfunction (Ref. Reference Shah and Brownlee107). Follicle-like protein 1 (FSTL1) is a glycosylated secretory protein produced by mesenchymal cell lines such as cardiomyocytes and fibroblasts. It is an acidic secretory protein rich in cysteine and is considered to be a beneficial regulator of cardiac fibrosis and insulin resistance. Recent studies have confirmed that the protective effect of FSTL1 in T2DM with MI was mediated by the USP10/Notch1 axis. Moreover, the inhibition of the USP10/Notch1 axis could counteract the myocardial protection of FSTL1 in T2DM (Ref. Reference Lu108).

Myocardial disease

Myocarditis is a local or diffuse inflammatory lesion of the heart characterized by inflammatory cell infiltration, cardiomyocyte degeneration and necrosis (Ref. Reference Sagar, Liu and Cooper109). In coxsackie virus B3 (CVB3)-infected myocarditis, the expression of miR-21 that targeted the mRNA of the deubiquitinase YOD1 was up-regulated, resulting in the downregulation of YOD1. The decreased expression of YOD1 led to the increase of the K48-linked ubiquitin chains of desmin protein, causing the degradation of desmin through the ubiquitin proteasome pathway. The degradation of desmin induced by YOD1 resulted in desmosome damage and disc dysfunction (Ref. Reference Nelson110).

Dilated cardiomyopathy (DCM) is a non-ischaemic cardiomyopathy with left ventricular dilation and systolic dysfunction, without coronary artery disease or abnormal load proportional to the degree of left ventricular damage (Ref. Reference Schultheiss111). By collecting myocardial samples from patients with DCM and volunteers in the control group, the researchers found that the protein level of p53 in patients with DCM was associated with the upregulation of herpesvirus-associated ubiquitin specific protease (HAUSP). HAUSP stabilized p53 by removing ubiquitin chains, resulting in increased cardiomyocyte apoptosis (Ref. Reference Birks112).

In DOX-induced cardiomyopathy, USP19 was downregulated in cardiomyocytes, which accelerated the degradation of TRAF2. The decrease in TRAF2 protein level led to abnormal NF-κB signalling, resulting in mitochondrial abnormalities and cell necrosis (Ref. Reference Dhingra113).

Rheumatic heart disease

Rheumatic heart disease (RHD) is a valvular heart disease caused by acute rheumatic fever (Ref. Reference Dooley114). It is an autoimmune sequela of suppurative streptococcal mucosal infection (Ref. Reference Carapetis115). As one of the CD4+ T cell subsets, Th17 secretes IL-17 to mediate inflammation as well as autoimmunity and promote inflammatory response as well as disease progression in patients with RHD. By isolating T cells from patients with RHD as well as healthy volunteers and detecting the mRNA level of USP4 in CD4+ T cells, the researchers found that the mRNA level of USP4 was related to the mRNA level of IL-17 and the function of Th17, indicating that USP4 may mediate the function of Th17 under inflammatory stimulation. The preliminary study of USP4 provided experimental evidence that USP4 may be a future therapeutic target for RHD (Ref. Reference Yang116).

Deubiquitinase inhibitors associated with cardiac disease

There are approximately 30 types of deubiquitinase inhibitors (Ref. Reference Lange, Armstrong and Kulathu19), and most of the research on deubiquitinase inhibitors focuses on tumours (Refs Reference Harrigan18, Reference Wang117). In terms of heart disease, a recent study revealed that UCHL1 inhibitors inhibited a variety of signalling pathways related to myocardial hypertrophy and fibrosis, such as AKT, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3 and NF-κB, which alleviated hypertension-induced myocardial hypertrophy and fibrosis (Ref. Reference Han118). P22077 is the inhibitor of USP7 with the protective role in cardiac hypertrophy and cardiac remodelling. The deubiquitinase inhibitor repressed multiple signalling pathways such as AKT/ERK and TGF-β/SMAD2/collagen I/collagen III, NF-κB/NLRP3 and NAPDH oxides, leading to the inhibition of inflammation and oxidative stress (Ref. Reference Gu119).

As is exhibited in Table 1, there is little research on the role of deubiquitinase inhibitors in cardiac disease, especially in cardiac hypertrophy, and the vast majority of deubiquitinase inhibitors are still in the pre-clinical stage, with no clinical research on deubiquitinase in cardiac disease (Ref. Reference Harrigan18). Compared with other deubiquitinase inhibitor, the anti-hypertrophic role of LDN-57444, the inhibitor of UCHL1, seems more explicit. LDN-57444 may serve as a new therapeutic direction in the future.

Table 1. The function and mechanism of deubiquitinase involved in regulating cardiac disease

Several studies have shown that the accumulation of ubiquitinated proteins induced by deubiquitinase can lead to endoplasmic reticulum (ER) stress and activation of autophagy (Refs Reference Bhattacharya120, Reference Christianson and Ye121). Both broad-spectrum inhibitors of deubiquitinases and specific inhibitors of individual deubiquitinases can lead to an increase in the ubiquitination of total proteins, thereby activating ER stress, unfolded protein response and AMPK pathway-mediated autophagy (Refs Reference Jiang122, Reference Min123). In hepatocellular carcinoma, the deubiquitinase inhibitor bAP15 (a specific inhibitor of UCHL5 and USP14) or ML-323 (a specific inhibitor of USP1) could increase the ubiquitination level of total proteins and activate ER stress, thereby inhibiting the viability and migration of cancer cells (Refs Reference Ding124, Reference Wang125). However, currently, there is few relevant research focusing on the relationship between deubiquitinase inhibitors and ER stress and ER stress-related autophagy in cardiac disease. In the future, more research is needed to focus on the potential impact of deubiquitinase inhibitors on ER stress and its related autophagy in cardiac disease.

Deubiquitinase functions beyond the cardiac disease

Deubiquitinases not only participate in regulating cardiac disease but also play an indispensable role in other diseases, including vascular disease, cancer and neurodegenerative diseases (Refs Reference Wang25, Reference Liu126, Reference Zhu127). Among the vascular diseases that are closely related to cardiac disease, deubiquitinases have been proven to be related to the onset and disease progression of atherosclerosis, vascular calcification, aneurysm onset and disease progression (Ref. Reference Wang25). Furthermore, the emerging role of deubiquitinases in cancer is also a research hotspot. It is demonstrated that deubiquitinase USP25 promoted tumour growth of pancreatic cancer in conversion with HIF-1α (Ref. Reference Nelson128). Taken together, deubiquitinases target a variety of proteins, endowing them with the ability to regulate physiological and pathological processes such as eukaryotic cell division, differentiation and apoptosis. Further exploration of the role of deubiquitinases in cardiac disease is promising.

Conclusion

Deubiquitinases can recognize a variety of proteins related to the progression and pathophysiological process of cardiac disease, stabilize the protein by removing the ubiquitin chains, then affect the activation of the signal pathway that is downstream of the substrate protein, and finally regulate the basic biological processes such as inflammation, apoptosis and autophagy. According to an increasing number of studies, deubiquitinases were implicated in the regulation of the pathophysiology progression of cardiac disease, and its abundance changes in a variety of pathological stimuli, which then affects the post-translational modification of proteins in vivo. However, there are still many unknowns about the mechanism of deubiquitinases regulating cardiac disease that needs to be further explored. There is still a large span from animal experiments to human research. A deeper study of the mechanism on the role of deubiquitinases and the study of related inhibitors will contribute to providing new therapeutic targets for cardiac disease in the future.

Funding statement

This work was supported by the National Natural Science Foundation of China (NSFC 81974089), 2019 Wuhan Huanghe talents (outstanding young talents) and the Frontier Application Basic Project of the Wuhan Science and Technology Bureau (Grant No. 2020020601012235).

Competing interest

None.

References

Powers, ET et al. (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annual Review of Biochemistry 78, 959991.CrossRefGoogle ScholarPubMed
Fulda, S, Rajalingam, K and Dikic, I (2012) Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications. EMBO Molecular Medicine 4, 545556.CrossRefGoogle ScholarPubMed
Kolla, S et al. (2022) Assembly and function of branched ubiquitin chains. Trends in Biochemical Sciences 47, 759771.CrossRefGoogle ScholarPubMed
Yau, R and Rape, M (2016) The increasing complexity of the ubiquitin code. Nature Cell Biology 18, 579586.CrossRefGoogle ScholarPubMed
Mevissen, TET and Komander, D (2017) Mechanisms of deubiquitinase specificity and regulation. Annual Review of Biochemistry 86, 159192.CrossRefGoogle ScholarPubMed
Sun, T, Liu, Z and Yang, Q (2020) The role of ubiquitination and deubiquitination in cancer metabolism. Molecular Cancer 19, 146.CrossRefGoogle ScholarPubMed
Bello, AI et al. (2022) Deubiquitinases in neurodegeneration. Cells 11, 556.CrossRefGoogle ScholarPubMed
Zhu, B et al. (2020) Roles of ubiquitination and deubiquitination in regulating dendritic cell maturation and function. Frontiers in Immunology 11, 586613.CrossRefGoogle ScholarPubMed
Bi, HL et al. (2020) The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor. Science Advances 6, eaax4826.CrossRefGoogle ScholarPubMed
Zhang, DH et al. (2020) Deubiquitinase ubiquitin-specific protease 10 deficiency regulates Sirt6 signaling and exacerbates cardiac hypertrophy. Journal of the American Heart Association 9, e017751.CrossRefGoogle ScholarPubMed
Hershko, A and Ciechanover, A (1998) The ubiquitin system. Annual Review of Biochemistry 67, 425479.CrossRefGoogle ScholarPubMed
Salas-Lloret, D and Gonzalez-Prieto, R (2022) Insights in post-translational modifications: ubiquitin and SUMO. International Journal of Molecular Sciences 23, 3281.CrossRefGoogle ScholarPubMed
Martinez-Ferriz, A et al. (2022) Ubiquitin-mediated mechanisms of translational control. Seminars in Cell & Developmental Biology 132, 146154.CrossRefGoogle ScholarPubMed
Dang, F, Nie, L and Wei, W (2021) Ubiquitin signaling in cell cycle control and tumorigenesis. Cell Death & Differentiation 28, 427438.CrossRefGoogle ScholarPubMed
Loureiro, J and Ploegh, HL (2006) Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions. Advances in Immunology 92, 225305.CrossRefGoogle ScholarPubMed
Ebner, P, Versteeg, GA and Ikeda, F (2017) Ubiquitin enzymes in the regulation of immune responses. Critical Reviews in Biochemistry and Molecular Biology 52, 425460.CrossRefGoogle ScholarPubMed
Cockram, PE et al. (2021) Ubiquitination in the regulation of inflammatory cell death and cancer. Cell Death & Differentiation 28, 591605.CrossRefGoogle ScholarPubMed
Harrigan, JA et al. (2017) Deubiquitylating enzymes and drug discovery: emerging opportunities. Nature Reviews Drug Discovery 17, 5778.CrossRefGoogle ScholarPubMed
Lange, SM, Armstrong, LA and Kulathu, Y (2022) Deubiquitinases: from mechanisms to their inhibition by small molecules. Molecular Cell 82, 1529.CrossRefGoogle ScholarPubMed
Komander, D, Clague, MJ and Urbe, S (2009) Breaking the chains: structure and function of the deubiquitinases. Nature Reviews Molecular Cell Biology 10, 550563.CrossRefGoogle ScholarPubMed
Clague, MJ et al. (2013) Deubiquitylases from genes to organism. Physiological Reviews 93, 12891315.CrossRefGoogle ScholarPubMed
Wertz, IE and Murray, JM (2019) Structurally-defined deubiquitinase inhibitors provide opportunities to investigate disease mechanisms. Drug Discovery Today: Technologies 31, 109123.CrossRefGoogle ScholarPubMed
Young, MJ et al. (2019) The role of ubiquitin-specific peptidases in cancer progression. Journal of Biomedical Science 26, 42.CrossRefGoogle ScholarPubMed
Chen, R et al. (2022) Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation. Cell Death & Disease 13, 139.CrossRefGoogle ScholarPubMed
Wang, B et al. (2020) The role of deubiquitinases in vascular diseases. Journal of Cardiovascular Translational Research 13, 131141.CrossRefGoogle ScholarPubMed
Shin, JM et al. (2006) Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability. BMC Genomics 7, 292.CrossRefGoogle ScholarPubMed
Baek, KH et al. (2004) DUB-1A, a novel deubiquitinating enzyme subfamily member, is polyubiquitinated and cytokine-inducible in B-lymphocytes. Journal of Biological Chemistry 279, 23682376.CrossRefGoogle ScholarPubMed
Xie, W et al. (2022) CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart. Cell Reports 41, 111864.CrossRefGoogle ScholarPubMed
Zhu, L et al. (2019) Molecular biomarkers in cardiac hypertrophy. Journal of Cellular and Molecular Medicine 23, 16711677.CrossRefGoogle ScholarPubMed
Nakamura, M and Sadoshima, J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nature Reviews Cardiology 15, 387407.CrossRefGoogle ScholarPubMed
Bacmeister, L et al. (2019) Inflammation and fibrosis in murine models of heart failure. Basic Research in Cardiology 114, 19.CrossRefGoogle ScholarPubMed
Hu, Q et al. (2020) Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction. Circulation Research 126, 456470.CrossRefGoogle ScholarPubMed
Shi, S and Jiang, P (2022) Therapeutic potentials of modulating autophagy in pathological cardiac hypertrophy. Biomedicine & Pharmacotherapy 156, 113967.CrossRefGoogle ScholarPubMed
Yang, D et al. (2021) Mitochondria in pathological cardiac hypertrophy research and therapy. Frontiers in Cardiovascular Medicine 8, 822969.CrossRefGoogle ScholarPubMed
Gibb, AA and Hill, BG (2018) Metabolic coordination of physiological and pathological cardiac remodeling. Circulation Research 123, 107128.CrossRefGoogle ScholarPubMed
Klaeske, K et al. (2021) Differential regulation of myocardial E3 ligases and deubiquitinases in ischemic heart failure. Life 11, 1430.CrossRefGoogle ScholarPubMed
Xing, J et al. (2020) Overexpression of ubiquitin-specific protease 2 (USP2) in the heart suppressed pressure overload-induced cardiac remodeling. Mediators of Inflammation 2020, 4121750.CrossRefGoogle ScholarPubMed
Mukhopadhyay, H and Lee, NY (2020) Multifaceted roles of TAK1 signaling in cancer. Oncogene 39, 14021413.CrossRefGoogle ScholarPubMed
Li, J et al. (2022) GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway. Cell Death & Disease 13, 421.CrossRefGoogle ScholarPubMed
Li, L et al. (2015) TAK1 regulates myocardial response to pathological stress via NFAT, NFkappaB, and Bnip3 pathways. Scientific Reports 5, 16626.CrossRefGoogle ScholarPubMed
He, B et al. (2016) Ubiquitin-specific protease 4 is an endogenous negative regulator of pathological cardiac hypertrophy. Hypertension 67, 12371248.CrossRefGoogle ScholarPubMed
Jiang, YN et al. (2023) Loss of USP22 alleviates cardiac hypertrophy induced by pressure overload through HiF1-alpha-TAK1 signaling pathway. Biochimica et Biophysica Acta, Molecular Basis of Disease 1869, 166813.CrossRefGoogle ScholarPubMed
Zhao, S et al. (2022) S-nitrosylation of Hsp90 promotes cardiac hypertrophy in mice through GSK3beta signaling. Acta Pharmacologica Sinica 43, 19791988.CrossRefGoogle ScholarPubMed
Tariq, U, Uppulapu, SK and Banerjee, SK (2021) Role of GSK-3 in cardiac health: focusing on cardiac remodeling and heart failure. Current Drug Targets 22, 15681576.CrossRefGoogle ScholarPubMed
Antos, CL et al. (2002) Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences of the USA 99, 907912.CrossRefGoogle ScholarPubMed
Duda, P et al. (2020) Targeting GSK3 and associated signaling pathways involved in cancer. Cells 9, 1110.CrossRefGoogle ScholarPubMed
Thornton, TM et al. (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320, 667670.CrossRefGoogle ScholarPubMed
Liu, N et al. (2016) Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3beta phosphorylation. Biochemical and Biophysical Research Communications 478, 12361241.CrossRefGoogle ScholarPubMed
Yang, J et al. (2000) Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays. Circulation 102, 30463052.CrossRefGoogle ScholarPubMed
McGrath, MJ et al. (2003) Skeletal muscle LIM protein 1 (SLIM1/FHL1) induces alpha 5 beta 1-integrin-dependent myocyte elongation. American Journal of Physiology. Cell Physiology 285, C1513C1526.CrossRefGoogle ScholarPubMed
Isumi, Y et al. (2011) Transgenic overexpression of USP15 in the heart induces cardiac remodeling in mice. Biochemical and Biophysical Research Communications 405, 216221.CrossRefGoogle ScholarPubMed
Zhihao, L et al. (2020) SERCA2a: a key protein in the Ca(2+) cycle of the heart failure. Heart Failure Reviews 25, 523535.CrossRefGoogle ScholarPubMed
Sitsel, A et al. (2019) Structures of the heart specific SERCA2a Ca(2+)-ATPase. EMBO Journal 38, e100020.CrossRefGoogle ScholarPubMed
Stammers, AN et al. (2015) The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA). Canadian Journal of Physiology and Pharmacology 93, 843854.CrossRefGoogle ScholarPubMed
Ye, B et al. (2023) USP25 ameliorates pathological cardiac hypertrophy by stabilizing SERCA2a in cardiomyocytes. Circulation Research 132, 465480.CrossRefGoogle ScholarPubMed
Han, J et al. (2023) Deubiquitinase JOSD2 improves calcium handling and attenuates cardiac hypertrophy and dysfunction by stabilizing SERCA2a in cardiomyocytes. Nature Cardiovascular Research 2, 764777.CrossRefGoogle Scholar
Guo, Z et al. (2022) SIRT6 In aging, metabolism, inflammation and cardiovascular diseases. Aging and Disease 13, 17871822.CrossRefGoogle ScholarPubMed
Tang, X et al. (2017) SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 136, 20512067.CrossRefGoogle ScholarPubMed
Mei, ZL et al. (2020) CSN6 aggravates Ang II-induced cardiomyocyte hypertrophy via inhibiting SIRT2. Experimental Cell Research 396, 112245.CrossRefGoogle ScholarPubMed
Wang, M et al. (2023) OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. Theranostics 13, 22632280.CrossRefGoogle ScholarPubMed
Lu, P et al. (2021) De-ubiquitination of p300 by USP12 critically enhances METTL3 expression and Ang II-induced cardiac hypertrophy. Experimental Cell Research 406, 112761.CrossRefGoogle ScholarPubMed
Miyamoto, S (2019) Autophagy and cardiac aging. Cell Death & Differentiation 26, 653664.CrossRefGoogle ScholarPubMed
Colombo, E et al. (2021) The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling. Proceedings of the National Academy of Sciences of the USA 118, e2110755118.CrossRefGoogle ScholarPubMed
Liu, Y et al. (2023) USP13 deficiency impairs autophagy and facilitates age-related lung fibrosis. American Journal of Respiratory Cell and Molecular Biology 68, 4961.CrossRefGoogle ScholarPubMed
Ming, SL et al. (2022) Inhibition of USP14 influences alphaherpesvirus proliferation by degrading viral VP16 protein via ER stress-triggered selective autophagy. Autophagy 18, 18011821.CrossRefGoogle Scholar
Qi, L et al. (2020) CYLD exaggerates pressure overload-induced cardiomyopathy via suppressing autolysosome efflux in cardiomyocytes. Journal of Molecular and Cellular Cardiology 145, 5973.CrossRefGoogle ScholarPubMed
Wang, H et al. (2015) Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2. Journal of Molecular and Cellular Cardiology 84, 143153.CrossRefGoogle ScholarPubMed
Guo, S et al. (2022) Epidermal growth factor receptor-dependent maintenance of cardiac contractility. Cardiovascular Research 118, 12761288.CrossRefGoogle ScholarPubMed
Schreier, B et al. (2013) Loss of epidermal growth factor receptor in vascular smooth muscle cells and cardiomyocytes causes arterial hypotension and cardiac hypertrophy. Hypertension 61, 333340.CrossRefGoogle ScholarPubMed
Peng, K et al. (2016) Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II. Journal of Cellular and Molecular Medicine 20, 482494.CrossRefGoogle ScholarPubMed
Xie, J et al. (2019) Cx32 mediates norepinephrine-promoted EGFR-TKI resistance in a gap junction-independent manner in non-small-cell lung cancer. Journal of Cellular Physiology 234, 2314623159.CrossRefGoogle Scholar
Hnatiuk, AP et al. (2022) Reengineering ponatinib to minimize cardiovascular toxicity. Cancer Research 82, 27772791.CrossRefGoogle ScholarPubMed
Kabuta, T et al. (2013) Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity. Journal of Biological Chemistry 288, 1261512626.CrossRefGoogle ScholarPubMed
Zhang, X et al. (2014) Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation. PLoS ONE 9, e94658.CrossRefGoogle ScholarPubMed
Liu, C et al. (2021) Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke. Journal of Zhejiang University. Science. B 22, 718732.CrossRefGoogle ScholarPubMed
Rajagopalan, V et al. (2013) Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure. American Journal of Physiology. Heart and Circulatory Physiology 305, H551H562.CrossRefGoogle ScholarPubMed
Cilenti, L et al. (2011) Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination. Journal of Molecular and Cellular Cardiology 50, 652661.CrossRefGoogle ScholarPubMed
Xue, Q et al. (2021) USP7, negatively regulated by miR-409-5p, aggravates hypoxia-induced cardiomyocyte injury. APMIS 129, 152162.CrossRefGoogle ScholarPubMed
Hu, Y et al. (2021) USP47 promotes apoptosis in rat myocardial cells after ischemia/reperfusion injury via NF-kappaB activation. Biotechnology and Applied Biochemistry 68, 841848.CrossRefGoogle ScholarPubMed
Zhao, W-K et al. (2021) Ferroptosis: opportunities and challenges in myocardial ischemia-reperfusion injury. Oxidative Medicine and Cellular Longevity 2021, 112.Google ScholarPubMed
Tang, L-J et al. (2021) Ubiquitin-specific protease 7 promotes ferroptosis via activation of the p53/TfR1 pathway in the rat hearts after ischemia/reperfusion. Free Radical Biology and Medicine 162, 339352.CrossRefGoogle ScholarPubMed
Liu, L et al. (2023) Deubiquitinase OTUD5 as a novel protector against 4-HNE-triggered ferroptosis in myocardial ischemia/reperfusion injury. Advanced Science 10, e2301852.CrossRefGoogle ScholarPubMed
Zhang, Y et al. (2023) Ubiquitin-specific protease 11 aggravates ischemia-reperfusion-induced cardiomyocyte pyroptosis and injury by promoting TRAF3 deubiquitination. Balkan Medical Journal 40, 205214.CrossRefGoogle ScholarPubMed
Ni, Y et al. (2015) The deubiquitinase USP17 regulates the stability and nuclear function of IL-33. International Journal of Molecular Sciences 16, 2795627966.CrossRefGoogle ScholarPubMed
Yang, J et al. (2019) LncRNA ANRIL knockdown relieves myocardial cell apoptosis in acute myocardial infarction by regulating IL-33/ST2. Cell Cycle 18, 33933403.CrossRefGoogle ScholarPubMed
Jin, Q et al. (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biology 14, 576587.CrossRefGoogle ScholarPubMed
Zhang, W et al. (2019) USP49 inhibits ischemia-reperfusion-induced cell viability suppression and apoptosis in human AC16 cardiomyocytes through DUSP1-JNK1/2 signaling. Journal of Cellular Physiology 234, 65296538.CrossRefGoogle ScholarPubMed
Travers, JG et al. (2016) Cardiac fibrosis: the fibroblast awakens. Circulation Research 118, 10211040.CrossRefGoogle ScholarPubMed
Hanna, A and Frangogiannis, NG (2019) The role of the TGF-β superfamily in myocardial infarction. Frontiers in Cardiovascular Medicine 6, 140.CrossRefGoogle ScholarPubMed
Xie, S et al. (2022) Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia-reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination. Acta Pharmaceutica Sinica. B 12, 41384153.CrossRefGoogle ScholarPubMed
Zhao, X et al. (2020) Targeting metabolic dysregulation for fibrosis therapy. Nature Reviews. Drug Discovery 19, 5775.CrossRefGoogle ScholarPubMed
Chen, ZT et al. (2021) Glycolysis inhibition alleviates cardiac fibrosis after myocardial infarction by suppressing cardiac fibroblast activation. Frontiers in Cardiovascular Medicine 8, 701745.CrossRefGoogle ScholarPubMed
Ji, JJ et al. (2022) Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation. Biochimica et Biophysica Acta, Molecular Basis of Disease 1868, 166441.CrossRefGoogle ScholarPubMed
Wang, F et al. (2023) Upregulation of glycolytic enzyme PFKFB3 by deubiquitinase OTUD4 promotes cardiac fibrosis post myocardial infarction. Journal of Molecular Medicine 101, 743756.CrossRefGoogle ScholarPubMed
Benoit, L et al. (2023) Experimental and clinical aspects of sevoflurane preconditioning and postconditioning to alleviate hepatic ischemia-reperfusion injury: a scoping review. International Journal of Molecular Sciences 24, 2340.CrossRefGoogle ScholarPubMed
Song, S et al. (2022) Role of sevoflurane in myocardial ischemia-reperfusion injury via the ubiquitin-specific protease 22/lysine-specific demethylase 3A axis. Bioengineered 13, 1336613383.CrossRefGoogle ScholarPubMed
Wang, X et al. (2018) Inflammation, autophagy, and apoptosis after myocardial infarction. Journal of the American Heart Association 7, e008024.CrossRefGoogle ScholarPubMed
Liu, CY et al. (2018) LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nature Communications 9, 29.CrossRefGoogle ScholarPubMed
Wu, P et al. (2022) Ubiquitin carboxyl-terminal hydrolase L1 of cardiomyocytes promotes macroautophagy and proteostasis and protects against post-myocardial infarction cardiac remodeling and heart failure. Frontiers in Cardiovascular Medicine 9, 866901.CrossRefGoogle ScholarPubMed
Ritchie, RH and Abel, ED (2020) Basic mechanisms of diabetic heart disease. Circulation Research 126, 15011525.CrossRefGoogle ScholarPubMed
Dillmann, WH (2019) Diabetic cardiomyopathy. Circulation Research 124, 11601162.CrossRefGoogle ScholarPubMed
Gupta, R et al. (2022) Protein S-sulfhydration: unraveling the prospective of hydrogen sulfide in the brain, vasculature and neurological manifestations. Ageing Research Reviews 76, 101579.CrossRefGoogle ScholarPubMed
Sun, Y et al. (2020) Exogenous H2S promoted USP8 sulfhydration to regulate mitophagy in the hearts of db/db mice. Aging and Disease 11, 269285.CrossRefGoogle ScholarPubMed
Choong, OK et al. (2019) Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction. Theranostics 9, 65506567.CrossRefGoogle ScholarPubMed
Yin, Q et al. (2022) YB-1 as an oncoprotein: functions, regulation, post-translational modifications, and targeted therapy. Cells 11, 1217.CrossRefGoogle ScholarPubMed
Zhong, X et al. (2022) ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1. Journal of Biological Chemistry 298, 101989.CrossRefGoogle ScholarPubMed
Shah, MS and Brownlee, M (2016) Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circulation Research 118, 18081829.CrossRefGoogle ScholarPubMed
Lu, L et al. (2021) FSTL1-USP10-Notch1 signaling axis protects against cardiac dysfunction through inhibition of myocardial fibrosis in diabetic mice. Frontiers in Cell and Developmental Biology 9, 757068.CrossRefGoogle ScholarPubMed
Sagar, S, Liu, PP and Cooper, LT Jr (2012) Myocarditis. Lancet 379, 738747.CrossRefGoogle ScholarPubMed
Nelson, JA et al. (2014) Coxsackievirus-induced miR-21 disrupts cardiomyocyte interactions via the downregulation of intercalated disk components. PLoS Pathogens 10, e1004070.Google Scholar
Schultheiss, HP et al. (2019) Dilated cardiomyopathy. Nature Reviews Disease Primers 5, 32.CrossRefGoogle ScholarPubMed
Birks, EJ et al. (2008) Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy. Cardiovascular Research 79, 472480.CrossRefGoogle ScholarPubMed
Dhingra, R et al. (2022) Proteasomal degradation of TRAF2 mediates mitochondrial dysfunction in doxorubicin-cardiomyopathy. Circulation 146, 934954.CrossRefGoogle ScholarPubMed
Dooley, LM et al. (2021) Rheumatic heart disease: a review of the current status of global research activity. Autoimmunity Reviews 20, 102740.CrossRefGoogle ScholarPubMed
Carapetis, JR et al. (2016) Acute rheumatic fever and rheumatic heart disease. Nature Reviews Disease Primers 2, 15084.CrossRefGoogle ScholarPubMed
Yang, J et al. (2015) Cutting edge: ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORgammat. Journal of Immunology 194, 40944097.CrossRefGoogle ScholarPubMed
Wang, X et al. (2018) Targeting deubiquitinase USP28 for cancer therapy. Cell Death & Disease 9, 186.CrossRefGoogle ScholarPubMed
Han, X et al. (2020) Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats. Hypertension Research 43, 10891098.CrossRefGoogle ScholarPubMed
Gu, Y-H et al. (2022) Administration of USP7 inhibitor P22077 inhibited cardiac hypertrophy and remodeling in Ang II-induced hypertensive mice. Frontiers in Pharmacology 13, 1021361.CrossRefGoogle ScholarPubMed
Bhattacharya, U et al. (2022) The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress. npj Precision Oncology 6, 1021361.CrossRefGoogle ScholarPubMed
Christianson, JC and Ye, Y (2014) Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nature Structural & Molecular Biology 21, 325335.CrossRefGoogle ScholarPubMed
Jiang, S et al. (2015) Participation of proteasome-ubiquitin protein degradation in autophagy and the activation of AMP-activated protein kinase. Cellular Signalling 27, 11861197.CrossRefGoogle ScholarPubMed
Min, H et al. (2014) Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemotherapy and Pharmacology 74, 167176.CrossRefGoogle ScholarPubMed
Ding, Y et al. (2018) Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum (ER) stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells. European Journal of Pharmacology 825, 1018.CrossRefGoogle Scholar
Wang, L et al. (2022) Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC. Cell Death & Disease 13, 951.CrossRefGoogle ScholarPubMed
Liu, B et al. (2022) Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases. Molecular Psychiatry 27, 259268.CrossRefGoogle ScholarPubMed
Zhu, W et al. (2021) Emerging roles of ubiquitin-specific protease 25 in diseases. Frontiers in Cell and Developmental Biology 9, 698751.CrossRefGoogle ScholarPubMed
Nelson, JK et al. (2022) USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nature Communications 13, 2070.CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. The main deubiquitinases involved in the pathogenesis of cardiac hypertrophy. Notes: Multiple deubiquitinases regulate cardiac hypertrophy through mechanisms such as autophagy, ROS, RNA methylation, signal transduction, and calcium homeostasis. CYLD: cylindromatosis; mTOR: mammalian target of rapamycin; Rab7: Ras-related protein Rab-7a; Erk: extracellular signal-regulated kinase; Nrf2: nuclear factor erythroid-2-related factor 2; USP: ubiquitin-specific protease; METTL3: metallothionein-like 3; GSK3β: Glycogen synthase kinase 3β; UCHL1: ubiquitin C-terminal hydrolases L1; EGFR: epidermal growth factor receptor; HIF-1α: hypoxia inducible factor-1α; TAK1: transforming growth factor-β-activated kinase 1; JNK1/2: c-Jun N-terminal kinase 1/2; SIRT6: sirtuin 6; AKT: protein kinase B; JOSD2: josephin domain-containing protein 2; SERCA2a: sarco/endoplasmic reticulum Ca2+-ATPase.

Figure 1

Figure 2. The main deubiquitinases involved in the development of myocardial infarction. Notes: A series of deubiquitinases regulate myocardial infarction through apoptosis, ferroptosis, pyroptosis or metabolic reprogramming. USP: ubiquitin-specific protease; TRAF3: TNF receptor-associated factor 3; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; OTUD: ovarian tumor-related deubiquitinase; NF-κB: nuclear factor kappa-B; TfR1: transferrin receptor 1; GPX4: glutathione peroxidase 4; DUSP1: dual specificity phosphatase 1; JNK1/2: c-Jun N-terminal kinase 1/2; UCHL1: ubiquitin C-terminal hydrolases L1.

Figure 2

Table 1. The function and mechanism of deubiquitinase involved in regulating cardiac disease