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 p21^WAF1/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 p21^WAF1/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).