Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes

Kawaguchi, Tomonori; Takemura, Genzou; Kanamori, Hiromitsu; Takahashi, Toshiaki; Watanabe, Takatomo; Morishita, Kentaro; Oginö, Kazuhíde; Tsujimoto, Akiko; Goto, Kazuko; Maruyama, Rumi; Kawasaki, Masanori; Mikami, Atsushi; Fujiwara, Takako; Fujiwara, Hisayoshi; Minatoguchi, Shinya

doi:10.1093/cvr/cvs282

Cited by 155 publications

(143 citation statements)

References 43 publications

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“…15 To confirm whether the observed increase in LC3 dots was due to increased autophagosome formation or impairment of their degradation, we measured in vivo autophagic flux in db/db hearts. 16,17 Under a short-term (4 h) intervention with chloroquine, greater numbers of LC3 dots were immunohistochemically evident in db/C than db/db hearts, and western blot analysis confirmed increased expression of LC3-II in db/C hearts, but not in db/db hearts (Fig. 9).…”

Section: Functional and Structural Profiles Of Hearts From Diabetic Micementioning

confidence: 95%

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Kanamori¹,

Takemura

Goto³

et al. 2015

Autophagy

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204

168

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Abbreviations: AMPK, AMP-activated protein kinase; CTSD, cathepsin D; DM, diabetes mellitus; GFP, green fluorescent protein; HBA1c, glycated hemoglobin a 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LV, left ventricular; MTOR, mechanistic target of rapamycin; SIRT1, sirtuin 1; Mn-SOD, superoxide dismutase 2, mitochondrial; STZ, streptozotocin; SQSTM1/p62, sequestosome 1.Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electronmicroscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/C mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.

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Section: Functional and Structural Profiles Of Hearts From Diabetic Micementioning

confidence: 95%

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Kanamori¹,

Takemura

Goto³

et al. 2015

Autophagy

Self Cite

204

168

View full text Add to dashboard Cite

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“…Indeed, Raffaghello et al [28] reported that 48-60 h of complete fasting prevented organ toxicity induced by chemotherapy in various species of female mice, however, etoposide rather than Dox was used in the study. Kawaguchi et al [29] demonstrated that 48 h of complete fasting prior to Dox administration mitigated the Dox-induced impairment in cardiac function in adult GFP-LC-3 transgenic mice, as determined by left ventricular ejection fraction (LVEF), systolic pressure (LVSP), end diastolic pressure (LVEDP), and +dP/dt. Microscopy revealed attenuation of LV dilatation, myocardial atrophy, and fibrosis [29] .…”

Section: Dox-induced Cardiotoxicitymentioning

confidence: 99%

“…Kawaguchi et al [29] demonstrated that 48 h of complete fasting prior to Dox administration mitigated the Dox-induced impairment in cardiac function in adult GFP-LC-3 transgenic mice, as determined by left ventricular ejection fraction (LVEF), systolic pressure (LVSP), end diastolic pressure (LVEDP), and +dP/dt. Microscopy revealed attenuation of LV dilatation, myocardial atrophy, and fibrosis [29] . In vitro, a caloric restriction mimetic, 2-deoxyglucose (2-DG), was shown to exhibit cardioprotective properties against Dox using neonatal rat cardiomyocytes isolated from 0-2 d old Harlan Sprague-Dawley rat neonates [30] .…”

Section: Dox-induced Cardiotoxicitymentioning

confidence: 99%

“…Kawaguchi et al [29] concluded that the protection against Dox-induced injury extended by 48-h of fasting prior to treatment was due to restoration of autophagy. Autophagy is a conserved process among eukaryotic cells that sequesters cellular material via formation of a multimembrane-bound vacuole, an autophagosome, followed by degradation of the material via fusion of the autophagosome with a lysosome [43] .…”

Section: Mechanism Of Fasting-induced Cardioprotection Against Dox Tomentioning

confidence: 99%

“…Indeed, stimulation of autophagy has been shown to be cardioprotective from a variety of damaging stimuli [44] . Kawaguchi et al [29] reported that the inhibition of autophagy by Dox was due to inhibition of AMP-activated protein kinase (AMPK). Prior fasting prevented the Dox-induced inhibition of AMPK.…”

Section: Mechanism Of Fasting-induced Cardioprotection Against Dox Tomentioning

confidence: 99%

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Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Dirks‐Naylor

Kouzi

Yang

et al. 2014

WJBC

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a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Fasting; Doxorubicin; Cardiotoxicity; Cardioprotection Core tip: Doxorubicin (Dox)-induced cardiotoxicity remains a significant cause of morbidity and mortality in cancer survivors, despite the intensive investigation of potential protective strategies. Studies have shown that shortterm fasting induces cardioprotective effects against Doxinduced injury. Importantly, evidence suggests that fasting may enhance the antitumor effects of Dox. Thus, shortterm fasting may be a feasible practice that can easily be incorporated into the treatment plans of cancer patients. Abstract Doxorubicin (Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as

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Lysosome Dysfunction: An Emerging Mechanism of Xenobiotic‐Induced Toxicity

Jessen

Will

et al. 2016

Lysosomes: Biology, Diseases, and Therapeutics

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Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes

Abstract: Prior starvation mitigates acute doxorubicin cardiotoxicity; the underlying mechanism may be, at least in part, restoration and further augmentation of myocardial autophagy, which is impaired by doxorubicin, probably through inactivation of AMP-activated protein kinase and ULK1.

Cited by 155 publications

References 43 publications

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Lysosome Dysfunction: An Emerging Mechanism of Xenobiotic‐Induced Toxicity

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