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Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts

Coelho, Ana R ; Martins, Tatiana R ; Couto, Renata ; Deus, Cláudia ; Pereira, Cláudia V ; Simões, Rui F LU ; Rizvanov, Albert A ; Silva, Filomena ; Cunha-Oliveira, Teresa and Oliveira, Paulo J , et al. (2017) In Biochimica et Biophysica Acta - Molecular Basis of Disease 1863(11). p.2904-2923
Abstract

Doxorubicin (DOX) is one of the most widely used anti-neoplastic agents. However, treatment with DOX is associated with cumulative cardiotoxicity inducing progressive cardiomyocyte death. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates the activity of proteins involved in apoptosis, autophagy and metabolism. Our hypothesis is that pharmacological modulation by berberine (BER) pre-conditioning of Sirt3 protein levels decreases DOX-induced cardiotoxicity. Our results showed that DOX induces cell death in all experimental groups. Increase in Sirt3 content by transfection-mediated overexpression decreased DOX cytotoxicity, mostly by maintaining mitochondrial network integrity and reducing oxidative stress. p53 was upregulated by... (More)

Doxorubicin (DOX) is one of the most widely used anti-neoplastic agents. However, treatment with DOX is associated with cumulative cardiotoxicity inducing progressive cardiomyocyte death. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates the activity of proteins involved in apoptosis, autophagy and metabolism. Our hypothesis is that pharmacological modulation by berberine (BER) pre-conditioning of Sirt3 protein levels decreases DOX-induced cardiotoxicity. Our results showed that DOX induces cell death in all experimental groups. Increase in Sirt3 content by transfection-mediated overexpression decreased DOX cytotoxicity, mostly by maintaining mitochondrial network integrity and reducing oxidative stress. p53 was upregulated by DOX, and appeared to be a direct target of Sirt3, suggesting that Sirt3-mediated protection against cell death could be related to this protein. BER pre-treatment increased Sirt3 and Sirt1 protein levels in the presence of DOX and inhibited DOX-induced caspase 9 and 3-like activation. Moreover, BER modulated autophagy in DOX-treated H9c2 cardiomyoblasts. Interestingly, mitochondrial biogenesis markers were upregulated in in BER/DOX-treated cells. Sirt3 over-expression contributes to decrease DOX cytotoxicity on H9c2 cardiomyoblasts, while BER can be used as a modulator of Sirtuin function and cell quality control pathways to decrease DOX toxicity.

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publishing date
type
Contribution to journal
publication status
published
keywords
Berberine/pharmacology, Cardiotonic Agents/pharmacology, Cell Line, Doxorubicin/adverse effects, Humans, Muscle Proteins/metabolism, Myoblasts, Cardiac/enzymology, Oxidative Stress/drug effects, Sirtuin 3/metabolism
in
Biochimica et Biophysica Acta - Molecular Basis of Disease
volume
1863
issue
11
pages
2904 - 2923
publisher
Elsevier
external identifiers
  • scopus:85030726008
  • pmid:28760703
ISSN
0925-4439
DOI
10.1016/j.bbadis.2017.07.030
language
English
LU publication?
no
id
811338f8-4c28-4684-aa7a-eb68da526e12
date added to LUP
2021-09-21 19:24:53
date last changed
2024-03-23 10:14:34
@article{811338f8-4c28-4684-aa7a-eb68da526e12,
  abstract     = {{<p>Doxorubicin (DOX) is one of the most widely used anti-neoplastic agents. However, treatment with DOX is associated with cumulative cardiotoxicity inducing progressive cardiomyocyte death. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates the activity of proteins involved in apoptosis, autophagy and metabolism. Our hypothesis is that pharmacological modulation by berberine (BER) pre-conditioning of Sirt3 protein levels decreases DOX-induced cardiotoxicity. Our results showed that DOX induces cell death in all experimental groups. Increase in Sirt3 content by transfection-mediated overexpression decreased DOX cytotoxicity, mostly by maintaining mitochondrial network integrity and reducing oxidative stress. p53 was upregulated by DOX, and appeared to be a direct target of Sirt3, suggesting that Sirt3-mediated protection against cell death could be related to this protein. BER pre-treatment increased Sirt3 and Sirt1 protein levels in the presence of DOX and inhibited DOX-induced caspase 9 and 3-like activation. Moreover, BER modulated autophagy in DOX-treated H9c2 cardiomyoblasts. Interestingly, mitochondrial biogenesis markers were upregulated in in BER/DOX-treated cells. Sirt3 over-expression contributes to decrease DOX cytotoxicity on H9c2 cardiomyoblasts, while BER can be used as a modulator of Sirtuin function and cell quality control pathways to decrease DOX toxicity.</p>}},
  author       = {{Coelho, Ana R and Martins, Tatiana R and Couto, Renata and Deus, Cláudia and Pereira, Cláudia V and Simões, Rui F and Rizvanov, Albert A and Silva, Filomena and Cunha-Oliveira, Teresa and Oliveira, Paulo J and Serafim, Teresa L}},
  issn         = {{0925-4439}},
  keywords     = {{Berberine/pharmacology; Cardiotonic Agents/pharmacology; Cell Line; Doxorubicin/adverse effects; Humans; Muscle Proteins/metabolism; Myoblasts, Cardiac/enzymology; Oxidative Stress/drug effects; Sirtuin 3/metabolism}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2904--2923}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta - Molecular Basis of Disease}},
  title        = {{Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts}},
  url          = {{http://dx.doi.org/10.1016/j.bbadis.2017.07.030}},
  doi          = {{10.1016/j.bbadis.2017.07.030}},
  volume       = {{1863}},
  year         = {{2017}},
}