PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy

Li, Qian; Li, Zhuo-ming; Sun, Shihui; Wang, Luping; Wang, Panxia; Guo, Zhen; Yang, Hanwei; Ye, Jiantao; Lü, Jing

doi:10.1038/s41401-018-0044-4

Cited by 13 publications

(7 citation statements)

References 44 publications

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“…Recent evidence has suggested that PARP1 facilitated LPS‐induced HMGB1 release via acetylation modification 26,27 . Besides, the interaction between PARP1 and HMGB1 proteins has also been reported 28,29 …”

Section: Introductionmentioning

confidence: 96%

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

Qiu

Qin

et al. 2021

J Cellular Molecular Medi

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Introduction Septic cardiomyopathy is a common complication of sepsis with high morbidity and mortality, but lacks specific therapy. This study aimed to reveal the role of circTLK1 and its potential mechanisms in septic cardiomyopathy. Materials and Methods The in vitro and in vivo models of septic cardiomyopathy were established. Cell viability and apoptosis were detected by CCK8, TUNEL and flow cytometry, respectively. LDH, CK, SOD, MDA, ATP, 8‐OHdG, NAD+/NADH ratio, ROS level, mitochondrial membrane potential and cytochrome C distribution were evaluated using commercial kits. qRT‐PCR and western blotting were performed to detect RNA and protein levels. Mitochondrial DNA (mtDNA) copy number and transcription were assessed by quantitative PCR. Dual‐luciferase assay, RNA immunoprecipitation and co‐immunoprecipitation were performed to verify the interaction between circTLK1/PARP1 and miR‐17‐5p. Results CircTLK1, PARP1 and HMGB1 were up‐regulated in the in vitro and in vivo models of septic cardiomyopathy. CircTLK1 inhibition restrained LPS‐induced up‐regulation of PARP1 and HMGB1. Moreover, circTLK1 knockdown repressed sepsis‐induced mtDNA oxidative damage, mitochondrial dysfunction and consequent cardiomyocyte apoptosis by inhibiting PARP1/HMGB1 axis in vitro and in vivo. In addition, circTLK1 enhanced PARP1 expression via sponging miR‐17‐5p. Inhibition of miR‐17‐5p abolished the protective effects of circTLK1 silencing on oxidative mtDNA damage and cardiomyocyte apoptosis. Conclusion CircTLK1 sponged miR‐17‐5p to aggravate mtDNA oxidative damage, mitochondrial dysfunction and cardiomyocyte apoptosis via activating PARP1/HMGB1 axis during sepsis, indicating that circTLK1 may be a putative therapeutic target for septic cardiomyopathy.

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Section: Introductionmentioning

confidence: 96%

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

Qiu

Qin

et al. 2021

J Cellular Molecular Medi

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“…5-BrdU (Beijing Solarbio Science & Technology Co., Ltd.) was added to a final concentration of 0.1 mmol/l to prevent the growth of fibroblasts, and the cells were further cultured in an incubator. According to previous studies (20)(21)(22)(23)(24) ) was used as the secondary antibody and incubated with the membrane at 4˚C for 2 h. The results were detected with enhanced chemiluminescence reagents (Wanleibio Co., Ltd.). Finally, membranes were scanned using a Bio-Rad image analyzer; and densitometry analysis was performed using Quantity One version 4.4 (Bio-Rad Laboratories, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…Thus, the effects of the ERK1/2 signaling pathway on the manner by which AA attenuates PCAF mediated-H3K9ac hyperacetylation in PE-induced hypertrophic cardiomyocytes was determined. First, according to the previous literature (21)(22)(23)(24), the optimum concentration of the histone acetylase inhibitor AA was determined (50 µmol/l), as well as for the ERK inhibitor U0126 (10 µmol/l), in accordance with H3K9ac levels, and the viability of myocardial cells using western blotting and CCK-8 examination, respectively (Fig. 2A and B).…”

Section: P-erk1/2 Interacts With Pcaf and Altered H3k9ac Acetylation In Hypertrophic Cardiomyocytes Induced By Pementioning

confidence: 99%

Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

Mao

Chang

et al. 2021

Mol Med Rep

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Cardiomyocyte hypertrophy is a compensatory phase of chronic heart failure that is induced by the activation of multiple signaling pathways. The extracellular signal-regulated protein kinase (ERK) signaling pathway is an important regulator of cardiomyocyte hypertrophy. In our previous study, it was demonstrated that phenylephrine (PE)-induced cardiomyocyte hypertrophy involves the hyperacetylation of histone H3K9ac by P300/CBP-associated factor (PCAF). However, the upstream signaling pathway has yet to be fully identified. In the present study, the role of the extracellular signal-regulated protein kinase (ERK)1/2 signaling pathway in PE-induced cardiomyocyte hypertrophy was investigated. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. The results showed that phospho-(p-)ERK1/2 interacted with PCAF and modified the pattern of histone H3K9ac acetylation. An ERK inhibitor (U0126) and/or a histone acetylase inhibitor (anacardic acid; AA) attenuated the overexpression of phospho-ERK1/2 and H3K9ac hyperacetylation by inhibiting the expression of PCAF in PE-induced cardiomyocyte hypertrophy. Moreover, U0126 and/or AA could attenuate the overexpression of several biomarker genes related to cardiac hypertrophy (myocyte enhancer factor 2C, atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain) and prevented cardiomyocyte hypertrophy. These results revealed a novel mechanism in that AA protects against PE-induced cardiomyocyte hypertrophy in mice via the ERK1/2 signaling pathway, and by modifying the acetylation of H3K9ac. These findings may assist in the development of novel methods for preventing and treating hypertrophic cardiomyopathy.

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“…PARP1, a member of PARP enzyme family, can modulate diverse biological processes through covalent transfer of ADP-ribose from NAD + onto substrate proteins or DNA chain, known as poly(ADP-ribosyl)ation (PARylation) 21 , 22 , 23 . Our previous studies have revealed that PARP1 is activated and PARylates FOXO3, STAT3 and HMGB1 in cardiac hypertrophy, whereas inhibition of PARP1 by 3-aminobenzamide (3AB) and veliparib (ABT-888) prevents the development of cardiac hypertrophy 24 , 25 , 26 , 27 . The observations of BRD4/PARP1 interaction thus prompt our hypothesis that BRD4 might act as a substrate protein of PARP1, and that PARylation of BRD4 by PARP1 might facilitate the recruitment of BRD4 to hyper-acetylated chromatin and enhance RNA Pol II phosphorylation, ultimately promoting transcription activation of hypertrophic biomarkers.…”

Section: Introductionmentioning

confidence: 99%

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

Guo

Lan

et al. 2021

Acta Pharmaceutica Sinica B

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The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

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PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy

Cited by 13 publications

References 44 publications

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

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