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Cathepsin B aggravated doxorubicin?induced myocardial injury via NF??B signalling.

ABSTRACT: Myocyte apoptosis and oxidative stress key critical roles in the process of doxorubicin (DOX)?induced cardiotoxicity. However, how apoptosis and oxidative stress arise in DOX?induced heart injury remains largely unknown. Cathepsin B (CTSB) is a typical lysosomal cysteine protease that is associated with apoptosis, inflammatory responses, oxidative stress and autophagy. The present study aimed to investigate the role of CTSB in DOX?induced heart injury and its potential mechanism. H9C2 cells were infected with adenovirus or transfected with small interfering RNA to overexpress or knock down CTSB, respectively, and then stimulated with DOX. DOX induced increased CTSB expression levels in H9C2 cells. DOX?induced cardiomyocyte apoptosis and oxidative stress were attenuated by CTSB knockdown but aggravated by CTSB overexpression in vitro. Mechanistically, the present study showed that CTSB activated the NF??B pathway in response to DOX. In summary, CTSB aggravated DOX?induced H9C2 cell apoptosis and oxidative stress via NF??B signalling. CTSB constitutes a potential therapeutic target for the treatment of DOX?induced cardiotoxicity.

SUBMITTER: Liu C

PROVIDER: S-EPMC7646931 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Cathepsin B aggravated doxorubicin‑induced myocardial injury via NF‑κB signalling.

Liu Chen C Cai Zhulan Z Hu Tongtong T Yao Qi Q Zhang Lijun L

Molecular medicine reports 20201011 6

Myocyte apoptosis and oxidative stress key critical roles in the process of doxorubicin (DOX)‑induced cardiotoxicity. However, how apoptosis and oxidative stress arise in DOX‑induced heart injury remains largely unknown. Cathepsin B (CTSB) is a typical lysosomal cysteine protease that is associated with apoptosis, inflammatory responses, oxidative stress and autophagy. The present study aimed to investigate the role of CTSB in DOX‑induced heart injury and its potential mechanism. H9C2 cells were ...[more]

PMID: 33173960

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Project description:AimsThe chemotherapy drug doxorubicin (Dox) is commonly used for treating a variety of human cancers; however, it is highly cardiotoxic and induces heart failure. We previously reported that the Bcl-2 mitochondrial death protein Bcl-2/19kDa interaction protein 3 (Bnip3), is critical for provoking mitochondrial perturbations and necrotic cell death in response to Dox; however, the underlying mechanisms had not been elucidated. Herein, we investigated mechanism that drives Bnip3 gene activation and downstream effectors of Bnip3-mediated mitochondrial perturbations and cell death in cardiac myocytes treated with Dox.Methods and resultsNuclear factor-κB (NF-κB) signalling, which transcriptionally silences Bnip3 activation under basal states in cardiac myocytes was dramatically reduced following Dox treatment. This was accompanied by Bnip3 gene activation, mitochondrial injury including calcium influx, permeability transition pore (mPTP) opening, loss of nuclear high mobility group protein 1, reactive oxygen species production, and cell death. Interestingly, impaired NF-κB signalling in cells treated with Dox was accompanied by protein complexes between Bnip3 and cyclophilin D (CypD). Notably, Bnip3-mediated mPTP opening was suppressed by inhibition of CypD-demonstrating that CypD functionally operates downstream of Bnip3. Moreover, restoring IKKβ-NF-κB activity in cardiac myocytes treated with Dox suppressed Bnip3 expression, mitochondrial perturbations, and necrotic cell death.ConclusionsThe findings of the present study reveal a novel signalling pathway that functionally couples NF-κB and Dox cardiomyopathy to a mechanism that is mutually dependent upon and obligatorily linked to the transcriptional control of Bnip3. Our findings further demonstrate that mitochondrial injury and necrotic cell death induced by Bnip3 is contingent upon CypD. Hence, maintaining NF-κB signalling may prove beneficial in reducing mitochondrial dysfunction and heart failure in cancer patients undergoing Dox chemotherapy.

Dataset Information

Cathepsin B aggravated doxorubicin?induced myocardial injury via NF??B signalling.

Publications

Cathepsin B aggravated doxorubicin‑induced myocardial injury via NF‑κB signalling.

Similar Datasets

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