Quantitative proteomic study identified cathepsin B associated with doxorubicin-induced damage in H9c2 cardiomyocytes

Bao, Guangyu; Wang, Huaizhou; Shang, Yongfeng; Fan, Huajie; Gu, Mingli; Xiao, Rong; Qin, Qin; Deng, Anmei

doi:10.5582/bst.2012.v6.6.283

Cited by 9 publications

(10 citation statements)

References 17 publications

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“…Proteomic profiling in H9c2 cardiomyocytes revealed that cathepsin B, a transcriptional target of Foxo1, was increased by doxorubicin (Bao et al . ). In other studies, short‐term exercise was shown to prevent doxorubicin‐induced elevation of mRNA levels of Foxo1 and MuRF‐1, which are atrophic factors of the heart (Kavazis et al .…”

Section: Introductionmentioning

confidence: 97%

Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

Sin

Tam

Yung

et al. 2015

The Journal of Physiology

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Key pointsr Doxorubicin induced functional deteriorations and elevations of USP7-related apoptotic/catabolic signalling in the senescent heart r Resveratrol protects against doxorubicin-induced alterations through the restoration of SIRT1 deacetylase activity Abstract A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1 activity to attenuate USP7-related catabolic/pro-apoptotic signalling. AbbreviationsAMPK, AMP-activated protein kinase; DR, doxorubicin + resveratrol; DRE, doxorubicin + resveratrol + EX527; DRS, doxorubicin + resveratrol + sirtinol; DV, doxorubicin and vehicle; EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricle end-diastolic dimension; LVESD, left ventricle end-systolic dimension; SAMP8, senescence-accelerated mice prone 8; SC, saline control; SIRT1, sirtuin 1; TBST, Tris-buffered saline with 0.1% Tween 20; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling.

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Section: Introductionmentioning

confidence: 97%

Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

Sin

Tam

Yung

et al. 2015

The Journal of Physiology

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“…CTSB is reportedly involved in various pathologies and oncogenic processes in humans (22,25). Moreover, increased CTSB expression was reported in H9c2 cardiomyocytes in patients with doxorubicininduced cardiomyopathy (2) and in patients with heart failure secondary to dilated cardiomyopathy (12). More recently, Liu et al (17) found that a specific CTSB inhibitor, CA-074Me, significantly attenuated cardiac remodeling after myocardial infarction.…”

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confidence: 99%

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

Yuan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Cathepsin B (CTSB), a member of the lysosomal cathepsin family that is expressed in both murine and human hearts, was previously shown to participate in apoptosis, autophagy, and the progression of certain types of cancers. Recently, CTSB has been linked to myocardial infarction. Given that cathepsin L, another member of the lysosomal cathepsin family, ameliorates pathological cardiac hypertrophy, we hypothesized that CTSB plays a role in pressure overload-induced cardiac remodeling. Here we report that CTSB was upregulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro. Moreover, knockout of CTSB attenuated pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and apoptosis. Furthermore, the aortic banding-induced activation of TNF-α, apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), c-Jun, and release of cytochrome c was blunted by CTSB deficiency, which was further confirmed in in vitro studies induced by angiotensin II. In cardiomyocytes pretreatment with SP600125, a JNK inhibitor, suppressed the cardiomyocytes hypertrophy by inhibiting the ASK1/JNK pathway. Altogether, these data indicate that the CTSB protein functions as a necessary modulator of hypertrophic response by regulating TNF-α/ASK1/JNK signaling pathway involved in cardiac remodeling.

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“…[7][8][9][10] Surprisingly, however, studies that validate the appropriateness of H9C2 as a model for cardiomyocytes by analysing global gene or protein expression changes during their differentiation, and relating these changes to physiological cardiomyocyte function, are rather sparse. [11][12][13] As one example, a recent iTRAQ-based mass spectrometry study by Lenco and colleagues questioned the applicability of H9C2 cells to cardiac research. 13 Specifically, they identified a lack of sufficient expression of proteins essential for formation of striated muscle cells and muscular metabolism in H9C2 cardiomyoblasts compared to primary cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics and systems analysis of cultured H9C2 cardiomyoblasts during differentiation over time supports a ‘function follows form’ model of differentiation

et al. 2018

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The rat cardiomyoblast cell line H9C2 has emerged as a valuable tool for studying cardiac development, mechanisms of disease and toxicology. We present here a rigorous proteomic analysis that monitored the changes in protein expression during differentiation of H9C2 cells into cardiomyocyte-like cells over time. Quantitative mass spectrometry followed by gene ontology (GO) enrichment analysis revealed that early changes in H9C2 differentiation are related to protein pathways of cardiac muscle morphogenesis and sphingolipid synthesis. These changes in the proteome were followed later in the differentiation time-course by alterations in the expression of proteins involved in cation transport and beta-oxidation.

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Quantitative proteomic study identified cathepsin B associated with doxorubicin-induced damage in H9c2 cardiomyocytes

Cited by 9 publications

References 17 publications

Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

Quantitative proteomics and systems analysis of cultured H9C2 cardiomyoblasts during differentiation over time supports a ‘function follows form’ model of differentiation

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