AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis

Liu, Dong; Ma, Zhiqiang; Di, Shouyin; Yang, Yang; Yang, Jingzhou; Xu, Liqun; Reíter, Russel J.; Qiao, Shubin; Yuan, Jiansong

doi:10.1016/j.freeradbiomed.2018.08.032

Cited by 190 publications

(169 citation statements)

References 45 publications

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“…Therefore, cardiac tissue with enriched mitochondrial content is more susceptible to anthracyclines, such as Dox, inducing cytotoxicity. It has been reported that Dox treatment causes increased ROS and lower MMP levels . The results of this experiment displayed a significant up‐regulation of ROS levels in Dox‐treated H9c2 cells and mouse hearts, along with MMP decreases.…”

Section: Discussionsupporting

confidence: 52%

“…In fact, a study conducted by Tan et al showed that in a cohort of women treated with anthracyclines and trastuzumab, left ventricular end‐diastolic and end‐systolic volumes increased, while ejection fraction, strain and strain rate decreased at the end of treatment compared with baseline. There, no recovery was present during >2 years follow‐up . It has been demonstrated that Dox induces cardiomyocyte toxicity and cell death through a variety of mechanisms, the most prominent being the production of excess reactive oxygen species (ROS) .…”

Section: Introductionmentioning

confidence: 99%

“…Mel also abrogates diabetic cardiomyopathy, by reducing ROS level and rescuing impaired mitophagy activity . Additional studies also showed Mel being involved in alleviating mitochondrial oxidative damage and apoptosis caused by Dox in cardiomyocytes . However, the exact mechanism mediating this protective effect of Mel on Dox‐induced cardiotoxicity remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…There, no recovery was present during >2 years follow-up. 2,3 It has been demonstrated that Dox induces cardiomyocyte toxicity and cell death through a variety of mechanisms, the most prominent being the production of excess reactive oxygen species (ROS). 4 Cardiac tissue contains abundant mitochondria, which are essential for cardiomyocytes to sustain sufficient ATP production for contractile function and cell survival.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Wang

Park

et al. 2020

J Cellular Molecular Medi

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There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin‐induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL‐positive cells, down‐regulation of anti‐apoptotic protein Bcl‐2, as well as up‐regulation of pro‐apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin‐melatonin co‐treatment alleviated in vivo doxorubicin‐induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down‐regulated Yes‐associated protein (YAP) expression, while YAP levels were maintained under co‐treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin‐treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Wang

Park

et al. 2020

J Cellular Molecular Medi

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“…In this study, AMPK phosphorylation was increased by DOX, though the treatment scheme both in their cell and in vivo models was far more severe than usually employed methods (10 μM DOX in cells and 4 weekly intraperitoneal injections of 8 mg/kg DOX in mice), which may explain the counterintuitive findings. Recently, the endogenous sleep-regulating hormone melatonin, which also has anti-oxidant capacity, was shown to reduce DOX cardiotoxicity in both rat H9c2 cardiomyoblasts and in C57BL/6 mice, via upregulation of AMPK/PGC1a signalling [92]. Oleuropein, which is a natural phenolic compound, reduced DOX-induced cardiotoxicity in Wistar rats and this was attributed to AMPK activation and a reversal of oxidative stress, apoptosis and impaired protein synthesis [93].…”

Section: Ampk Activation By Other Compoundsmentioning

confidence: 99%

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Timm

Tyler

2020

Cardiovasc Drugs Ther

129

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Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

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Rational Engineering of a Mitochondrial‐Mimetic Therapy for Targeted Treatment of Dilated Cardiomyopathy by Precisely Regulating Mitochondrial Homeostasis

Chen

et al. 2023

Adv Funct Materials

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Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for heart transplantation. Currently, there is still an unmet clinical need in effective therapies for DCM. Herein a mitochondrial‐mimetic therapy capable of efficiently targeting the heart, cardiomyocytes, and myocardial mitochondria as well as effectively regulating mitochondrial homeostasis for targeted treatment of DCM is reported. A bioactive conjugate TPT is first synthesized by integrating three functional moieties onto a scaffold, which can assemble into small‐size nanomicelles (i.e., TPTN). Intravenously delivered TPTN efficiently accumulates in the heart and mainly localizes in cardiomyocytes and myocardial mitochondria of DCM mice, thereby alleviating DCM. Mechanistically, TPTN inhibits intracellular oxidative stress, alleviates mitochondrial injury, improves mitochondrial dynamics, regulates mitochondrial oxidative phosphorylation, and reduces calpain‐1 and NLRP3 inflammasome activation, thus restoring mitochondrial homeostasis and inhibiting adverse cardiac remodeling. By packaging TPTN into outer mitochondrial membrane‐derived vesicles, a mitochondrial‐mimetic therapy is engineered, which displays significantly enhanced three‐level targeting capability to the heart, cardiac cells, and myocardial mitochondria, thereby affording notably potentiated therapeutic effects in DCM mice. Accordingly, the three‐level targeting mimetics is promising for targeted treatment of DCM. The findings provide new insight into rational design of precision therapies for mitochondrial dysfunction‐associated diseases.

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AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis

Cited by 190 publications

References 45 publications

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Rational Engineering of a Mitochondrial‐Mimetic Therapy for Targeted Treatment of Dilated Cardiomyopathy by Precisely Regulating Mitochondrial Homeostasis

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