Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway.
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ABSTRACT:
SUBMITTER: Hu C
PROVIDER: S-EPMC6664099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15?mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3?/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5?mg/kg, i.p., once a week for three times, the total cumulative dose is 15?mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
| S-EPMC7206111 | biostudies-literature
Project description:The clinical use of doxorubicin for cancer therapy is limited by its cardiotoxicity, which involves cardiomyocyte apoptosis and oxidative stress. Previously, we showed that general control nonderepressible 2 (GCN2), an eukaryotic initiation factor 2α (eIF2α) kinase, impairs the ventricular adaptation to chronic pressure overload by affecting cardiomyocyte apoptosis. However, the impact of GCN2 on Dox-induced cardiotoxicity has not been investigated. In the present study, we treated wild type (WT) and Gcn2-/- mice with four intraperitoneal injections (5 mg/kg/week) to induce cardiomyopathy. After Dox treatment, Gcn2-/- mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of the Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and induction of its downstream targets, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and preserved the expression of anti-apoptotic factor Bcl-2 and mitochondrial uncoupling protein-2(UCP2). Furthermore, we found that GCN2 knockdown attenuated, whereas GCN2 overexpression exacerbated, Dox-induced cell death, oxidative stress and reduction of Bcl-2 and UCP2 expression through the eIF2α-CHOP-dependent pathway in H9C2 cells. Collectively, our data provide solid evidence that GCN2 has a marked effect on Dox induced myocardial apoptosis and oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in cardiomyocyte may provide a novel approach to attenuate Dox-related cardiotoxicity.
| S-EPMC6006681 | biostudies-literature
Project description:BackgroundInflammation, oxidative stress, and apoptosis contribute to the evolution of doxorubicin (DOX)-induced cardiotoxicity. Osteocrin (OSTN) is a novel secretory peptide mainly derived from the bone and skeletal muscle, and plays critical roles in regulating bone growth and physical endurance. Inspiringly, OSTN was also reported to be abundant in the myocardium that functioned as a therapeutic agent against cardiac rupture and congestive heart failure in mice after myocardial infarction. Herein, we investigated the role and potential mechanism of OSTN in DOX-induced cardiotoxicity.MethodsCardiac-restrict OSTN overexpression was performed by the intravenous injection of a cardiotropic AAV9 vector, and subsequently the mice received 15 mg/kg DOX injection (i.p., once) to induce acute cardiac injury. Besides, H9C2 cell lines were used to assess the possible role of OSTN in vitro by incubating with recombinant human OSTN or small interfering RNA against Ostn (siOstn). To clarify the involvement of protein kinase G (PKG), KT5823 and siPkg were used in vivo and in vitro. Mice were also administrated intraperitoneally with 5 mg/kg DOX weekly for consecutive 3 weeks at a cumulative dose of 15 mg/kg to mimic the cardiotoxic effects upon chronic DOX exposure.ResultsOSTN treatment notably attenuated, whereas OSTN silence exacerbated inflammation, oxidative stress, and cardiomyocyte apoptosis in DOX-treated H9C2 cells. Besides, cardiac-restrict OSTN-overexpressed mice showed an alleviated cardiac injury and malfunction upon DOX injection. Mechanistically, we found that OSTN activated PKG, while PKG inhibition abrogated the beneficial effect of OSTN in vivo and in vitro. As expected, OSTN overexpression also improved cardiac function and survival rate in mice after chronic DOX treatment.ConclusionsOSTN protects against DOX-elicited inflammation, oxidative stress, apoptosis, and cardiac dysfunction via activating PKG, and cardiac gene therapy with OSTN provides a novel therapeutic strategy against DOX-induced cardiotoxicity.
| S-EPMC7418805 | biostudies-literature
Project description:Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. Neonatal rat cardiomyocytes (CMs) and CFs were used to verify the protective effect of RA in vitro. Conditioned medium derived from RA-treated CFs were prepared to illustrate the effect of RA on paracrine interplay between CFs and CMs. We found that RA significantly alleviated DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in vivo, which, however, had almost negligible beneficial effect on DOX directly induced cardiomyocyte apoptosis in vitro. Mechanistically, CFs-derived Fas L was responsible for DOX-induced cardiomyocyte apoptosis, and RA treatment could decrease Fas L expression in CFs and its release to the conditioned medium by suppressing nuclear factor of activated T cells (NFAT) activation and metalloproteinase 7 (MMP7) expression, and exerted the anti-apoptotic effect on CMs via CFs. Ionomycin, and activator of NFAT, abrogated RA-mediated protective effect on cardiomyocyte apoptosis and cardiac dysfunction. In summary, RA alleviated cardiomyocyte apoptosis by inhibiting the expression and release of Fas L in CFs via a paracrine manner, moreover, NFAT as well as MMP7 inhibition were responsible for the suppression of Fas L. RA could be a powerful new therapeutic agent to mitigate cardiomyocyte apoptosis, thereby improving DOX-induced cardiotoxicity.
| S-EPMC6367577 | biostudies-literature
Project description:Doxorubicin (DOX) is a broad-spectrum, highly effective antitumor agent; however, its cardiotoxicity has greatly limited its use. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter that exerts cardioprotective effects via the regulation of oxidative stress and apoptosis and maintenance of mitochondrial function, among other mechanisms. AP39 is a novel mitochondria-targeted H2S donor that, at appropriate concentrations, attenuates intracellular oxidative stress damage, maintains mitochondrial function, and ameliorates cardiomyocyte injury. In this study, DOX-induced cardiotoxicity models were established using H9c2 cells and Sprague-Dawley rats to evaluate the protective effect of AP39 and its mechanisms of action. Both in vivo and in vitro experiments showed that DOX induces oxidative stress injury, apoptosis, and mitochondrial damage in cardiomyocytes and decreases the expression of p-AMPK/AMPK and UCP2. All DOX-induced changes were attenuated by AP39 treatment. Furthermore, the protective effect of AP39 was significantly attenuated by the inhibition of AMPK and UCP2. The results suggest that AP39 ameliorates DOX-induced cardiotoxicity by regulating the expression of AMPK/UCP2.
| S-EPMC10990198 | biostudies-literature
Project description:Resolvin D1 (RvD1) is a lipid mediator that promotes resolution of inflammation. However, the function of RvD1 in doxorubicin- (Dox-) induced cardiotoxicity remains to be clarified. This study aimed to investigate whether RvD1 could attenuate Dox-induced cardiac injury. The mice were divided into three groups: control, Dox (20 mg/kg, once, intraperitoneally), and Dox + RvD1. RvD1 (2.5 μg/kg, intraperitoneally) was injected daily for 5 days. Echocardiography was performed to evaluate the cardiac function, and the heart tissue and serum samples were collected for further analyses. The results showed that RvD1 attenuated the decreased ratio of heart weight/body weight and heart weight/tibia length, the increased level of creatine kinase and activity of lactate dehydrogenase after Dox treatment. RvD1 improved the ejection fraction and fractional shortening of left ventricular and attenuated the severity of apoptosis induced by Dox. As for the underlying pathways, the results showed that RvD1 reduced the expression of IL-1 and IL-6, and attenuated the phosphorylation of P65 in cardiac tissue. RvD1 attenuated the oxidative stress induced by Dox, as demonstrated by the attenuated levels of superoxide dismutase, glutathione, and malondialdehyde, decreased expression of Nox-2 and Nox-4 and increased expression of Nrf-2 and HO-1. In addition, RvD1 also inhibited the endoplasmic reticulum stress induced by Dox. These results indicate the potential therapeutic benefits of RvD1 in Dox-induced cardiotoxicity in mice, and the mechanism may be related to the attenuated inflammation, oxidative stress and endoplasmic reticulum stress.
| S-EPMC8769281 | biostudies-literature
Project description:Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its cardiotoxicity limits its clinical application. A better understanding of the molecular mechanisms underlying DOX cardiotoxicity will benefit clinical practice and remedy heart failure. Our present study observed that DOX caused cardiomyocyte (H9c2) apoptosis via the induction of abnormal mitochondrial fission. Notably, the expression levels of p21 increased in DOX-treated cardiomyocytes, and the silencing of p21 using siRNA greatly attenuated mitochondrial fission and apoptosis in cardiomyocytes. We also found that miR-499-5p could directly target p21 and attenuated DOX-induced mitochondrial fission and apoptosis. The role of the miR-499-5p-p21 axis in the prevention of DOX cardiotoxicity was also validated in the mice model. DOX treatment induced an upregulation of p21, which induced subsequent abnormal mitochondrial fission and myocardial apoptosis in mouse heart. Adenovirus-harboring miR-499-5p-overexpressing mice exhibited significantly reduced p21 expression, mitochondrial fission and myocardial apoptosis in hearts following DOX administration. The miR-499-5p-overexpressing mice also exhibited improved cardiomyocyte hypertrophy and cardiac function after DOX treatment. However, miR-499-5p was not involved in the DOX-induced apoptosis of cancer cells. Taken together, these findings reveal an emerging role of p21 in the regulation of mitochondrial fission program. miR-499-5p attenuated mitochondrial fission and DOX cardiotoxicity via the targeting of p21. These results provide new evidence for the miR-499-5p-p21 axis in the attenuation of DOX cardiotoxicity. The development of new therapeutic strategies based on the miR-499-5p-p21 axis is a promising path to overcome DOX cardiotoxicity as a chemotherapy for cancer treatment.
| S-EPMC6348261 | biostudies-literature
Project description:Background: As an effective antitumor drug, doxorubicin (DOX) is primarily used to treat solid tumors and hematologic malignancies. However, increasing evidence has emerged indicating its cardiotoxicity, and few solutions have been proposed to counter this side effect. Higenamine (HG) is a natural compound widely found in many Chinese herbs and also serves as a component in many healthcare products. Several studies have demonstrated its cardioprotective effect in different models, but little is known about the underlying influences of HG against myocardial damage from DOX-induced chronic cardiotoxicity. Methods and Results: C57BL/6 mice and neonatal rat ventricular cardiomyocytes (NRVMs) were used to evaluate the cardioprotective effect of HG against DOX-induced myocardial damage. In mice, DOX (intraperitoneally injected 5 mg/kg every 3 days for 4 weeks) significantly increased cardiomyocyte apoptosis, cardiac atrophy, and cardiac dysfunction, which were significantly attenuated by HG (intragastrically administered with 10 mg/kg every day for 4 weeks). In NRVMs, DOX (3 μM for 24 h) significantly increased cell apoptosis and the level of reactive oxygen species while reducing the level of superoxide dismutase and mitochondrial membrane potential. Remarkably, HG can reverse these pathological changes caused by DOX. Interestingly, the protective effect of HG on DOX-induced cardiotoxicity was independent of the activation of the beta-2 adrenergic receptor (β2-AR), known for mediating the effect of HG on antagonizing ischemia/reperfusion-induced cardiac apoptosis. Furthermore, HG attenuated the abnormal activation of phosphorylated adenosine-activated protein kinase (AMPK). Consistently, AMPK agonists (AICAR) can eliminate these pharmacological actions of HG. Conclusion: Collectively, our results suggested that HG alleviated DOX-induced chronic myocardial injury by suppressing AMPK activation and ROS production.
| S-EPMC9117701 | biostudies-literature
Project description:Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by in vivo studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.
| S-EPMC8818847 | biostudies-literature
Project description:Children surviving cancer and chemotherapy are at risk for adverse health events including heart failure that may be delayed by years. Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8-20 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced "late-onset cardiotoxicity" was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3-4 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1-45 mg/kg). Cardiovascular function was unaltered at the lower dosages (1-15 kg/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.
| S-EPMC7052608 | biostudies-literature