Wogonin reduces cardiomyocyte apoptosis from mitochondrial release of cytochrome c to improve doxorubicin‑induced cardiotoxicity

Abstract

Doxorubicin (DOX) has powerful anticancer properties, but its clinical application is affected by its serious cardiotoxicity. Wogonin (WG) has been shown to have marked cardiovascular protection potential. However, it is not known whether this potential can protect the heart from DOX damage. The aim of the present study was to investigate whether WG could ameliorate the cardiotoxicity of DOX. DOX and WG were used to establish a model of cardiac damage. Echocardiography, brain natriuretic peptide, creatine kinase MB and cardiac troponin T were used to detect the degree of cardiac damage. The levels of superoxide dismutase, malondialdehyde, glutathione and catalase in serum were measured to observed oxidative stress state. The mRNA levels of cyclophilin D, voltage-dependent anion-selective channel 1 and adenine nucleotide transporter 1 were detected by reverse transcription-quantitative PCR. Western blotting was used to detect the expression of cytochrome c in mitochondria and cytoplasm and cleaved-caspase-9 and pro/cleaved-caspase-3 in cytoplasm in cardiac tissue and primary cardiomyocytes to verify the related signaling pathways. DOX rats showed a series of cardiac damage. However, these damages were alleviated following WG treatment. Further studies showed that WG antagonized DOX cardiotoxicity through inhibiting the release of cytochrome c. WG protected rat heart from DOX damage. The mechanism may be closely related to inhibiting the release of cytochrome c from mitochondria and reducing cardiomyocyte apoptosis caused by caspase activation.

The beneficial role of exercise in preventing doxorubicin-induced cardiotoxicity

“…Cytochrome c in the inner membrane of mitochondria is released into the cytoplasm ( An et al, 2009 ). Subsequently, cytochrome c activates caspase-9, resulting in the activation of caspase-3 in DOX-treated cardiomyocytes ( Wei et al, 2022 ). These findings many explain how DOX treatment can induce cardiomyocyte apoptosis, which causes cardiotoxicity.…”

A bibliometric and visual analysis of research trends and hotspots of myocardial apoptosis: A review

“…Deng et al [28] used H9c2 cells and discovered that the noncoding repressor of nuclear factor of activated T cells up-regulated the expression of si-hypoxia-inducible factor-1 alpha (HIF-1 alpha), thereby alleviating cardiomyocyte apoptosis induced by hypoxia/ reoxygenation (H/R). Wei et al [29] employed Doxorubicin (DOX) to establish a rat heart injury model and found that Wogonin protected the rat heart from DOX-induced damage by inhibiting the release of mitochondrial cytochrome c and reducing the apoptosis of cardiomyocytes caused by caspase activation. Xu et al, [30] utilizing male C57/B6J mice, found that Shenfu injection up-regulated the expression of B-cell lymphoma-2 (Bcl-2) protein, thereby inhibiting myocardial apoptosis and mitigating mitochondrial damage induced by septicemia through downregulation of BH3 interacting domain death agonist and caspase-9 proteins.…”