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

Abstract

A B S T R A C TDoxorubicin (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.

Berberine suppresses apoptosis and extracellular matrix (ECM) degradation in nucleus pulposus cells and ameliorates disc degeneration in a rodent model

“…More recently, it was reported that BBR could alleviate high glucose-induced podocyte apoptosis via autophagy 15 . In addition, BBR can stimulate autophagy in various tissues including heart 16 , lungs 17 and hepar 18 , however, this has not been shown in the NP. Considering that oxidative stress, apoptosis and inflammatory activation are all elements of IVDD pathology, we hypothesize that BBR may utilize autophagy to prevent the formation of IVDD.…”

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

“…For example, dexrazoxane, an iron chelating agent against iron-mediated oxidative stress, is the cardio-protective medicine approved by FDA in July 1995 for preventing anthracycline-induced cardiotoxicity, and now has been widely applied in the clinical practice (Padegimas et al, 2020). In addition, numerous natural antioxidants serve as adjuvant therapies to reduce drug-induced cardiotoxicity, such as berberine, epigallocatechin-3-gallate, and resveratrol (Coelho et al, 2017;Yu et al, 2018).…”

SIRT3: A New Regulator of Cardiovascular Diseases

“…Polydatin, a monocrystalline and a polyphenolic drug extracted from the traditional Chinese herb Polygonum cuspidatum , protects cardiomyocytes against myocardial infarction injury by upregulating autophagy and improving mitochondrial biogenesis via SIRT3 activity [ 116 ]. Berberine decreases DOX-induced cardiotoxicity by activating SIRT3 [ 117 ]. Honokiol, a natural biphenolic compound derived from the bark of magnolia trees, blocks and reverses cardiac hypertrophy by activating SIRT3 [ 76 , 118 ].…”