Hydrogen sulfide ameliorates doxorubicin‑induced myocardial fibrosis in rats via the PI3K/AKT/mTOR pathway

Nie,Liangui; Liu,Maojun; Chen,Jian; Wu,Qian; Li,Yaling; Yi,Jiali; Zheng,Xia; Zhang,Jingjing; Chu,Chun; Yang,Jun

doi:10.3892/mmr.2021.11938

Hydrogen sulfide ameliorates doxorubicin‑induced myocardial fibrosis in rats via the PI3K/AKT/mTOR pathway

Authors:
- Liangui Nie
- Maojun Liu
- Jian Chen
- Qian Wu
- Yaling Li
- Jiali Yi
- Xia Zheng
- Jingjing Zhang
- Chun Chu
- Jun Yang
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Affiliations: Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China, Department of Pharmacy, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: February 24, 2021 https://doi.org/10.3892/mmr.2021.11938
Article Number: 299
Copyright: © Nie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to determine the role and regulatory mechanism of hydrogen sulfide (H₂S) in the amelioration of doxorubicin‑induced myocardial fibrosis in rats. It is hypothesized that the PI3K/AKT/mTOR signaling pathway is regulated to inhibit endoplasmic reticulum stress (ERS) and autophagy to reduce myocardial fibrosis. A total of 40 adult male Sprague Dawley rats were randomly divided into 4 groups (n=10/group). The 4 groups included the normal control group (control group), model group [doxorubicin (Dox) group], H₂S intervention model group (H₂S+Dox group) and H₂S control group (H₂S group). The model used in the present study was constructed by administering intraperitoneal injections of doxorubicin (3.0 mg/kg every other day; total of 6 injections). In addition, the intervention factor, NaHS and the donor of H₂S, was also administered by intraperitoneal injection (56 µmol/kg/day), which lasted a month. Pathological changes in the rats were observed using Masson staining and transmission electron microscopy, while the protein expression levels of MMPs/TIMPs, transforming growth factor‑β1, cystathionine lyase and PI3K/AKT/mTOR, which are autophagy‑related and ERS‑related proteins were detected in myocardial tissues using western blot analysis. The gene expression levels of collagen type I α‑2 chain and collagen type III α‑1 chain were detected using reverse transcription‑quantitative PCR and the quantification of myocardial H₂S content was performed using ELISA. In the Dox group compared with that in the control group, myocardial fibers were significantly disordered, while the protein expression levels of ERS‑related and autophagy‑related proteins were increased markedly, and the expression levels of PI3K/AKT/mTOR proteins were reduced markedly. The aforementioned changes were markedly reversed following H₂S intervention, which indicated that H₂S exerts a positive protective effect on doxorubicin‑induced myocardial fibrosis. The protective mechanism of H₂S intervention in myocardial fibrosis is hypothesized to be associated with the inhibition of overactivation of the ER and that of autophagy via upregulation of the PI3K/AKT/mTOR pathway.

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