HDAC6 inhibition protects cardiomyocytes against doxorubicin-induced acute damage by improving α-tubulin acetylation

Song, Rui; Yang, Yurong; Han, Ling; Wang, Guangxue; Huang, Yong; Xue, Wenlong; Wang, Yinfang; Yao, Lingling; Zhu, Yi‐Chun

doi:10.1016/j.yjmcc.2018.10.007

Cited by 48 publications

(39 citation statements)

References 38 publications

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“…It was found that acetyl-α-tubulin, which maintained microtubule homeostasis, was significantly reduced, which also preliminarily suggested that a high concentration of silicate might affect the acetylation of microtubule proteins, further leading to the disintegration of microtubules and thereby blocking the trafficking of autophagosomes to lysosomes. α-Tubulin acetylated modification was regulated by HDAC6 [45, 46], and our further research also confirmed that a high concentration of silicate can promote the expression of HDAC6. After using siRNA to interfere with HDAC6 expression, α-tubulin acetylation was enhanced significantly compared with silicate treatment alone, and the microtubule structure was also partially recovered with more beam-like divergent structures.…”

Section: Discussionsupporting

confidence: 68%

Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Liu

et al. 2019

Stem Cell Res Ther

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BackgroundSilicon-modified biomaterials have been extensively studied in bone tissue engineering. In recent years, the toxicity of silicon-doped biomaterials has gradually attracted attention but requires further elucidation. This study was designed to explore whether high-dose silicate can induce a cytotoxicity effect in bone mesenchymal stem cells (BMSCs) and the role of autophagy in its cytotoxicity and mechanism.MethodsMorphologic changes and cell viability of BMSCs were detected after different doses of silicate exposure. Autophagic proteins (LC3, p62), LC3 turnover assay, and RFP-GFP-LC3 assay were applied to detect the changes of autophagic flux following silicate treatment. Furthermore, to identify the potential mechanism of autophagic dysfunction, we tested the acetyl-α-tubulin protein level and histone deacetylase 6 (HDAC6) activity after high-dose silicate exposure as well as the changes in microtubule and autophagic activity after HDAC6 siRNA was applied.ResultsIt was found that a high dose of silicate could induce a decrease in cell viability; LC3-II and p62 simultaneously increased after high-dose silicate exposure. A high concentration of silicate could induce autophagic dysfunction and cause autophagosomes to accumulate via microtubule destabilization. Results showed that acetyl-α-tubulin decreased significantly with high-dose silicate treatment, and inhibition of HDAC6 activity can restore microtubule structure and autophagic flux.ConclusionsMicrotubule destabilization caused by a high concentration of silicate via HDAC6 activation contributed to autophagic dysfunction in BMSCs, and inhibition of HDAC6 exerted a cytoprotection effect through restoration of the microtubule structure and autophagic flux.

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Section: Discussionsupporting

confidence: 68%

Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Liu

et al. 2019

Stem Cell Res Ther

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“…DOX‐derived ROS causes an imbalance between pro‐ and anti‐apoptotic proteins (such as Bcl‐2 family), disrupting mitochondrial membrane potential, causing cytochrome c release and subsequently causing cell apoptosis . The heart has high energy requirement and a high mitochondrial density, which is more susceptible to DOX‐induced toxicity . With the treatment of YWPC, we found great improvement in the disordered and swelled mitochondria induced by DOX.…”

Section: Discussionmentioning

confidence: 91%

Yellow Wine Polyphenolic Compounds prevents Doxorubicin‐induced cardiotoxicity through activation of the Nrf2 signalling pathway

Lin

Zhang

et al. 2019

J Cellular Molecular Medi

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Doxorubicin (DOX) is considered as the major culprit in chemotherapy‐induced cardiotoxicity. Yellow wine polyphenolic compounds (YWPC), which are full of polyphenols, have beneficial effects on cardiovascular disease. However, their role in DOX‐induced cardiotoxicity is poorly understood. Due to their antioxidant property, we have been suggested that YWPC could prevent DOX‐induced cardiotoxicity. In this study, we found that YWPC treatment (30 mg/kg/day) significantly improved DOX‐induced cardiac hypertrophy and cardiac dysfunction. YWPC alleviated DOX‐induced increase in oxidative stress levels, reduction in endogenous antioxidant enzyme activities and inflammatory response. Besides, administration of YWPC could prevent DOX‐induced mitochondria‐mediated cardiac apoptosis. Mechanistically, we found that YWPC attenuated DOX‐induced reactive oxygen species (ROS) and down‐regulation of transforming growth factor beta 1 (TGF‐β1)/smad3 pathway by promoting nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) nucleus translocation in cultured H9C2 cardiomyocytes. Additionally, YWPC against DOX‐induced TGF‐β1 up‐regulation were abolished by Nrf2 knockdown. Further studies revealed that YWPC could inhibit DOX‐induced cardiac fibrosis through inhibiting TGF‐β/smad3‐mediated ECM synthesis. Collectively, our results revealed that YWPC might be effective in mitigating DOX‐induced cardiotoxicity by Nrf2‐dependent down‐regulation of the TGF‐β/smad3 pathway.

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“…Meanwhile, DOX suppressed lysosome acidification and autolysosome degradation, which blocked the autophagic flux and augmented the damage (Li et al, 2016). Moreover, DOX-induced upregulation of histone deacetylase 6 (HDAC6) decreased α-tubulin acetylation level, giving rise to mitochondrial dysfunction and autophagy flux damage (Song et al, 2018). Lysosome dysfunction was found to involve in the depletion of transcription factor EB (TFEB).…”

Section: Autophagymentioning

confidence: 99%

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Wei

Zhang

et al. 2020

Front. Cell Dev. Biol.

102

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Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

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HDAC6 inhibition protects cardiomyocytes against doxorubicin-induced acute damage by improving α-tubulin acetylation

Cited by 48 publications

References 38 publications

Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Yellow Wine Polyphenolic Compounds prevents Doxorubicin‐induced cardiotoxicity through activation of the Nrf2 signalling pathway

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

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