Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression.
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ABSTRACT:
SUBMITTER: Wang P
PROVIDER: S-EPMC7982427 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the hallmarks of doxorubicin-induced cardiotoxicity (DICT) is the cascade of mitophagy deficiency-mitochondrial oxidative injury-apoptosis, while so far, there is no preventive strategy for alleviating DICT by targeting this molecular mechanism. Excitedly, based on our previous drug screen in DICT zebrafish model, harpagoside (HAR) showed dramatic anti-DICT efficacy superior to dexrazoxane (DXZ) only cardioprotectant approved by FDA. Therefore, its pharmacological effects and molecular mechanism on DICT mouse and rat cardiomyocytes were further discussed. In vivo, HAR significantly improved cardiac function and myocardial structural lesions with concomitant of diminished mitochondrial oxidative damage and recovered mitophagy flux. In parallel, HAR protected mitophagy and mitochondria homeostasis, and repressed apoptosis in vitro. Intriguingly, both nutlin-3 (agonist of p53) and Parkin siRNA reversed these protective effects of HAR. Additional data, including fluorescence colocalization of Parkin and MitoTracker and mt-Keima for the detection of mitophagy flux and coimmunoprecipitation of p53 and Parkin, showed that HAR promoted Parkin translocation to mitochondria and substantially restored Parkin-mediated mitophagy by inhibiting the binding of p53 and Parkin. Importantly, the results of the cell viability demonstrated that cardioprotective effect of HAR did not interfere with anticancer effect of DOX on MCF-7 and HepG2 cells. Our research documented p53-Parkin-mediated cascade of mitophagy deficiency-mitochondrial dyshomeostasis-apoptosis as a pathogenic mechanism and druggable pathway and HAR as a cardioprotection on DICT by acting on novel interaction between p53 and Parkin.
| S-EPMC8867983 | biostudies-literature
Project description:Shenmai injection (SMI), as a patented traditional Chinese medicine, is extracted from Panax ginseng and Ophiopogon japonicus. It commonly used in the treatment of cardiovascular disease and in the control of cardiac toxicity induced by doxorubicin (DOX) treatment. However, its anti-cardiotoxicity mechanism remains unknown. The purpose of this study was to investigate the underlying mitochondrial protective mechanisms of SMI on DOX-induced myocardial injury. The cardioprotective effect of SMI against DOX-induced myocardial damage was evaluated in C57BL/6 mice and H9c2 cardiomyocytes. In vivo, myocardial injury, apoptosis and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt)/glycogen synthase kinase 3 beta (GSK-3β) signaling pathway related proteins were measured. In vitro, apoptosis, mitochondrial superoxide, mitochondrial membrane potential, mitochondrial morphology, levels of mitochondrial fission/fusion associated proteins, mitochondrial respiratory function, and AMP-activated protein kinase (AMPK) activity were assessed. To further elucidate the regulating effects of SMI on AMPK and PI3K/Akt/GSK-3β signaling pathway, compound C and LY294002 were utilized. In vivo, SMI decreased mortality rate, levels of creatine kinase, and creatine kinase-MB. SMI significantly prevented DOX-induced cardiac dysfunction and apoptosis, decreased levels of Bax/Bcl-2 and cleaved-Caspase3, increased levels of PI3K, p-Akt, and p-GSK-3β. In vitro, SMI rescued DOX-injured H9c2 cardiomyocytes from apoptosis, excessive mitochondrial reactive oxygen species production and descending mitochondrial membrane potential, which were markedly suppressed by LY294002. SMI increased ratio of L-OPA1 to S-OPA1, levels of AMPK phosphorylation, and DRP1 phosphorylation (Ser637) in order to prevent DOX-induced excessive mitochondrial fission and insufficient mitochondrial fusion. In conclusion, SMI prevents DOX-induced cardiotoxicity, inhibits mitochondrial oxidative stress and mitochondrial fragmentation through activation of AMPK and PI3K/Akt/GSK-3β signaling pathway.
| S-EPMC7289952 | biostudies-literature
Project description:Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague-Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.
| S-EPMC8719652 | biostudies-literature
Project description:Doxorubicin (DOX) is an effective anticancer agent. Its clinical use is, however, limited due to its detrimental side effects, especially the cardiotoxicity caused by ROS, mitochondrial dysfunction and apoptosis. 3',4'-dihydroxyflavonol (DiOHF) is a recently developed potent synthetic flavonoid which has been reported to exert anti-oxidative activity in myocardial ischemia-reperfusion injury and maintain the normal mitochondrial function. The aim of this study was to explore the protective effects of DiOHF on the DOX-induced cardiotoxicity. We established DOX-induced cardiotoxicity in H9C2 cells by incubation with 1 ?M DOX and in BALB/c mice by DOX injection. DiOHF effectively prevented and reversed the DOX-induced cardiotoxicity, including ROS production, mitochondrial dysfunction, and apoptosis. The DOX-induced cardiotoxicity was accompanied by ERK1/2 activation and abolished by the silence of ERK1, rather than ERK2. Furthermore, DOX treatment in mice induced an increase in serum CK-MB level and myocardial fibrosis with a reduction in left ventricular (LV) function. These detrimental effects were blunted by DiOHF administration. Conclusion: DiOHF suppresses and reverses the DOX-induced cardiotoxicity by inhibiting ROS release, stabilizing mitochondrial function and reducing apoptosis through activation of the ERK1 signaling.
| S-EPMC6777440 | biostudies-literature
Project description:The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague-Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.
| S-EPMC6663922 | biostudies-literature
Project description:The lysosomal cysteine protease Cathepsin K is elevated in humans and animal models of heart failure. Our recent studies show that whole-body deletion of Cathepsin K protects mice against cardiac dysfunction. Whether this is attributable to a direct effect on cardiomyocytes or is a consequence of the global metabolic alterations associated with Cathepsin K deletion is unknown. To determine the role of Cathepsin K in cardiomyocytes, we developed a cardiomyocyte-specific Cathepsin K-deficient mouse model and tested the hypothesis that ablation of Cathepsin K in cardiomyocytes would ameliorate the cardiotoxic side-effects of the anticancer drug doxorubicin. We used an α-myosin heavy chain promoter to drive expression of Cre, which resulted in over 80% reduction in protein and mRNA levels of cardiac Cathepsin K at baseline. Four-month-old control (Myh-Cre-; Ctsk fl/fl) and Cathepsin K knockout (Myh-Cre+; Ctsk fl/fl) mice received intraperitoneal injections of doxorubicin or vehicle, 1 week following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca2+-handling were evaluated. Control mice treated with doxorubicin exhibited a marked increase in cardiac Cathepsin K, which was associated with an impairment in cardiac structure and function, evidenced as an increase in end-systolic and end-diastolic diameters, decreased fractional shortening and wall thickness, disruption in cardiac sarcomere and microfilaments and impaired intracellular Ca2+ homeostasis. In contrast, the aforementioned cardiotoxic effects of doxorubicin were attenuated or reversed in mice lacking cardiac Cathepsin K. Mechanistically, Cathepsin K-deficiency reconciled the disturbance in cardiac energy homeostasis and attenuated NF-κB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease.
| S-EPMC5992138 | biostudies-literature
Project description:ObjectivesWe aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity.BackgroundDoxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists.MethodsLeft ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques.ResultsFive days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists.ConclusionsThese data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.
| S-EPMC2239316 | biostudies-literature
Project description:Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tragus vagus nerve stimulation (tVNS) improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 312 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.
| S-EPMC10904274 | biostudies-literature
Project description:Honokiol is a key component of a medicinal herb, Magnolia bark. Honokiol possesses potential pharmacological benefits for many disease conditions, especially cancer. Recent studies demonstrate that Honokiol exerts beneficial effects on cardiac hypertrophy and doxorubicin (Dox)-cardiotoxicity via deacetylation of mitochondrial proteins. However, the effects and mechanisms of Honokiol on cardiac mitochondrial respiration remain unclear. In the present study, we investigate the effect of Honokiol on cardiac mitochondrial respiration in mice subjected to Dox treatment. Oxygen consumption in freshly isolated mitochondria from mice treated with Honokiol showed enhanced mitochondrial respiration. The Dox-induced impairment of mitochondrial respiration was less pronounced in honokiol-treated than control mice. Furthermore, Luciferase reporter assay reveals that Honokiol modestly increased PPAR? transcriptional activities in cultured embryonic rat cardiomyocytes (H9c2). Honokiol upregulated the expression of PPAR? in the mouse heart. Honokiol repressed cardiac inflammatory responses and oxidative stress in mice subjected to Dox treatment. As a result, Honokiol alleviated Dox-cardiotoxicity with improved cardiac function and reduced cardiomyocyte apoptosis. We conclude that Honokiol protects the heart from Dox-cardiotoxicity via improving mitochondrial function by not only repressing mitochondrial protein acetylation but also enhancing PPAR? activity in the heart. This study further supports Honokiol as a promising therapy for cancer patients receiving Dox treatment.
| S-EPMC5607346 | biostudies-literature
Project description:Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tVNS improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 248 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.
2024-01-28 | GSE253959 | GEO