Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice

Bi, Hai-Lian; Zhang, Yunlong; Yang, Jie; Shu, Qing; Yang, Xiaolei; Yan, Xiao; Chen, Chen; Li, Zhi; Li, Huihua

doi:10.1038/s41440-019-0354-z

Cited by 27 publications

(20 citation statements)

References 37 publications

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“…The role of UCHL1 relies on the context of the cells. The antifibrotic role of LDN on the heart was also shown by another study that examined atrial fibrillation but did not use cell culture models 27 . In addition, the pro-activation effect of UCHL1 is observed in other types of fibroblasts, such as cancer-associated fibroblasts and hepatic stellate cells 29,32 .…”

Section: Discussionmentioning

confidence: 73%

“…To date, only a few studies have assessed the role of UCHL1 in heart diseases. One study found that UCHL1 was markedly upregulated in post-MI heart 26 and another suggested that UCHL1 acts as a regulator of the Ang II-induced atrial fibrillation and inhibition of it attenuated atrial fibrosis in vivo 27 . Inspired by the finding that the UCHL1 exerts both endogenous and exogenous pro-activation effects in hepatic stellate cells, which are a type of fibroblast 28,29 , we hypothesised that UCHL1 may promote cardiac fibrosis following MI via induction of CF activation.…”

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confidence: 99%

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Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)

Lei

Tao

et al. 2020

Sci Rep

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Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-β1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-β1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitationmass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-β1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI. Myocardial infarction (MI) has been the main cause of cardiovascular diseases for centuries and remains a major issue. Although improved survival from acute MI has been observed due to the effectiveness of revascularisation and other therapies, the incidence of heart failure has increased as a consequence of adverse ventricular remodelling 1,2. Among the factors involved in ventricular remodelling, cardiac fibrosis, which results from the disequilibrium of synthesis and deregulation of extracellular matrix, is a pivotal 3,4. In the acute stage, cardiac fibrosis, is a repairing process that protects the infarct heart from rupture; at the subacute and chronic stage, in cases where cardiac fibrosis abnormally persists, it inevitably leads to cardiac dysfunction and ventricular wall stiffness increasing the risk of heart failure 4,5. Thus, it is essential to control levels of cardiac fibrosis. Cardiac fibroblasts (CFs) are central mediators of the cardiac fibrotic response 6. CFs are mainly stimulated by TGFβ-1 following MI and differentiate into activated myofibroblasts which express α-smooth muscle actin (α-SMA). This results in the secretion of a large amount of extracellular matrix, including fibronectin and collagen I (Col1), which is, in part, regulated by the activation of Smad2/3 4,7,8. To date, no studies have fully elucidated how this process is regulated. The ubiquitin proteasome system (UPS), which consists of E1 ubiquitin-activating enzymes, E2 conjugating enzymes and E3 ubiquitin ligases and deubiquitinating enzymes, is responsible for the degradation and stability of the majority of proteins 9,10. Rece...

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Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)

Lei

Tao

et al. 2020

Sci Rep

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“…Expression of ERRFI1 [191], ALOX12 [192], SOCS5 [193], DDIT4 [194], DUSP4 [195], IL6ST [196], DUSP1 [197], SMAD1 [198], NCL (nucleolin) [199], METTL14 [200], FMOD (fibromodulin) [201], CYGB (cytoglobin) [202], UNC5A [203] and TAAR9 [204] are associated with prognosis in patients with diabetic nephropathy, but these genes might be novel target for T1DM. A previous study reported that FAP (fibroblast activation protein alpha) [205], EYA4 [206], BCL9 [207], IRF2BP2 [208], EGR3 [209], GADD45B [210], DMD (dystrophin) [211], LSR (lipolysis stimulated lipoprotein receptor) [212], DLL4 [213], SUN2 [214], SOS1 [215], PIK3CA [216], GAMT (guanidinoacetate N-methyltransferase) [217], RBM47 [218], HSP90AA1 [219], GAB1 [220], S1PR1 [221], EDNRB (endothelin receptor type B) [222], NFKBIA (NFKB inhibitor alpha) [223], GJA1 [224], GADD45G [225], PHLDA1 [226], CMPK2 [227], FIGN (fidgetin, microtubule severing factor) [228], KCNJ2 [229], ABCC9 [230], DIRAS3 [231], EPHX1 [232], RAB4A [233], UBIAD1 [234], CASQ2 [235], TTN (titin) [236], KCNH1 [237], JPH2 [238], OXGR1 [239], UCHL1 [240], SERPINA3 [241], MMP28 [242], ADAMTS2 [243], P2RY1 [244], CSF2RA [245], MYO1F [246], SELPLG (selectin P ligand) [247] and SAMHD1 [248] are expressed in cardiovascular disease, but these genes might be novel target for T1DM. MAOB (monoamine oxidase B) [249], VEGFC (vascular endothelial growth factor C) [250], DBP (D-box binding PAR bZIP transcription factor) [251], MYADM (myeloid associated differentiation marker) [252], NES (nestin) [253], SMURF1 [254], EDNRB (endothelin receptor type B) [255], MUC6 [25...…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

Bm¹,

Cm²

2021

Preprint

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Type 1 diabetes mellitus (T1DM) is a metabolic disorder for which the underlying molecular mechanisms remain largely unclear. This investigation aimed to elucidate essential candidate genes and pathways in T1DM by integrated bioinformatics analysis. In this study, differentially expressed genes (DEGs) were analyzed using DESeq2 of R package from GSE162689 of the Gene Expression Omnibus (GEO). Gene ontology (GO) enrichment analysis, REACTOME pathway enrichment analysis, and construction and analysis of protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network, and validation of hub genes were then performed. A total of 952 DEGs (477 up regulated and 475 down regulated genes) were identified in T1DM. GO and REACTOME enrichment result results showed that DEGs mainly enriched in multicellular organism development, detection of stimulus, diseases of signal transduction by growth factor receptors and second messengers, and olfactory signaling pathway. The top hub genes such as MYC, EGFR, LNX1, YBX1, HSP90AA1, ESR1, FN1, TK1, ANLN and SMAD9 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Receiver operating characteristic curve (ROC) analysis and RT-PCR confirmed that these genes were significantly associated with T1DM. In conclusion, the identified DEGs, particularly the hub genes, strengthen the understanding of the advancement and progression of T1DM, and certain genes might be used as candidate target molecules to diagnose, monitor and treat T1DM.

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“…Matuszczak et al (2018) found that UCHL1 may reflect the metabolic response to acute state inflammation in appendicitis patients. Bi et al (2020) found that UCHL1 inhibitor reduced inflammatory cell infiltration in mouse heart. Furthermore, UCHL1 expression was significantly higher in several inflammatory diseases of glomeruli (Y. Liu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

UCHL1 regulates inflammation via MAPK and NF‐κB pathways in LPS‐activated macrophages

Zhang

Liu

Chen

et al. 2021

Cell Biology International

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Inflammation is a common pathophysiological process as well as a clinical threat that occurs in various diseases worldwide. It is well‐documented that nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase pathways are involved in inflammatory reactions to microbial infections in lipopolysaccharide (LPS)‐activated macrophages. The deubiquitinase ubiquitin carboxyl‐terminal hydrolase‐L1 (UCHL1) has been reported as an oncoprotein to promote the growth and progression of cancer cells. However, the regulatory mechanism of UCHL1 in inflammation is currently unclear. Here, we aimed to assess the effects of UCHL1 on LPS‐associated inflammatory response in vitro and in vivo by enzyme‐linked immunosorbent assay, quantitative reverse‐transcription polymerase chain reaction, and western blot analysis. This study identified that inhibition or knockdown of UCHL1 decreased the amounts of the key pro‐inflammatory cytokines, including interleukin‐6 and tumor necrosis factor‐α in macrophages. Additionally, inhibition of UCHL1 suppressed LPS‐induced extracellular signal‑regulated protein kinase 1/2 phosphorylation and NF‐κB translocation by regulating the inhibitor of NF‐κB. Mechanically, UCHL1 interacts with IκBα protein in THP‐1. Meanwhile, inhibition of UCHL1 blocked the LPS‐induced degradation of IκBα through the ubiquitin‐proteasome system. Moreover, in vivo assay showed that suppression of UCHL1 notably reduced the LPS‐induced animal death and release of pro‐inflammatory cytokines. Overall, the current findings uncover that UCHL1 functions as a crucial regulator for inflammatory response via reversing the degradation of IκBα, representing a potential target for the treatment of inflammatory diseases.

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Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice

Cited by 27 publications

References 37 publications

Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)

Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

UCHL1 regulates inflammation via MAPK and NF‐κB pathways in LPS‐activated macrophages

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