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

Abstract

The present study aimed to determine the role and regulatory mechanism of hydrogen sulfide (H 2 S) 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], H 2 S intervention model group (H 2 S+Dox group) and H 2 S control group (H 2 S 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 H 2 S, 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 H 2 S 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 H 2 S intervention, which indicated that H 2 S exerts a positive protective effect on doxorubicin-induced myocardial fibrosis. The protective mechanism of H 2 S 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.

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…Further, the PI3K-AKT-mTOR signaling pathway has been found to participate in the DOX-induced skeleton muscle atrophy and cancer cachexia-related cardiac atrophy (112,113). DOX was reported to impair AKT-mTOR axis by several research (82,(114)(115)(116)(117). As reported, β2-agonist formoterol was reported to decrease protein degradation partially through inhibiting PI3K-AKT-mTOR mediated ALS, which prevented the muscle mass loss in fasted mice (118).…”

Oleoylethanolamide as a New Therapeutic Strategy to Alleviate Doxorubicin-Induced Cardiotoxicity

“…Consistent with these observations, we found that OEA increased expressions of PI3K and p-Akt in cardiomyocytes through a TRPV1-dependent way. Moreover, previous studies have shown that activation of PI3K/ Akt ameliorates doxorubicin-induced myocardial injury ( Sun et al, 2014 ; Liu et al, 2016 ; Sahu et al, 2019 ; Nie et al, 2021 ). Our data confirmed the contribution of PI3K/ Akt signaling in OEA-mediated protective effects, thereby supporting the proposed mechanism that OEA alleviates DIC through a TRPV1-mediated PI3K/ Akt pathway.…”

Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress

“…It is worth noting that when mitochondrial dysfunction occurs, the tricarboxylic acid cycle is inhibited, thereby promoting the remodelling of myocardial fibrosis, which is manifested by upregulation of MMP-9 and collagen I expression ( Liang et al, 2015 ). At this time, tricarboxylic acid cycle disorder can also activate autophagy-related proteins and ERS to promote myocardial fibrosis, and this pathophysiological effect of mitochondrial dysfunction can be reversed by NaHS ( Kumar et al, 2019 ; Nie et al, 2021 ). Ang-II inhibits miR-133a and induces mitochondrial oxidative stress and mtDNA damage in cardiomyocytes, and these Ang-II-induced pathophysiological effects can also be reversed by NaHS ( Ceylan-Isik et al, 2013 ; Su et al, 2021 ).…”