CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1

Yao, Yuan; Ma, Zhen‐Guo; Zhang, Xin; Xu, Si-Chi; Zeng, Xiaofeng; Zheng, Yang; Deng, Wei; Tang, Qi‐Zhu

doi:10.1016/j.yjmcc.2017.10.008

Cited by 128 publications

(125 citation statements)

References 39 publications

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“…Previous studies also demonstrated that DOX could induce apoptosis via mechanisms that do not directly involve ROS production and oxidative stress [8]. Our recent study also revealed that suppression of cardiomyocyte apoptosis significantly attenuated DOX-induced cardiac dysfunction [9]. Therefore, an intensive understanding of the pathogenesis of DOX-induced oxidative stress and cardiomyocyte apoptosis, and the identification of novel therapeutic targets are urgently needed.…”

Section: Introductionmentioning

confidence: 85%

“…All mice were maintained under specific pathogen-free, environmentally controlled (Temperature: 20-25°C; Humidity: 50 ± 5%) barrier conditions in individual ventilated cages and were fed with sterile food and water ad libitum. To specifically overexpress FNDC5 in the myocardium, mice received a single intravenous injection of adeno-associated virus 9 (AAV9) carrying human FNDC5 under the cTnT promoter (AAV9-FNDC5) or a negative control (AAV9-NC) via the tail vein at a concentration of 1 × 10 11 viral genome per mouse [9]. The AAV9-FNDC5 and AAV9-NC were generated by Hanbio Biotechnology Co. (Shanghai, China).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

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FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

et al. 2019

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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/GSK3β/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.

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Section: Introductionmentioning

confidence: 85%

Section: Animals and Treatmentsmentioning

confidence: 99%

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

et al. 2019

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“…In particular, Doxo can cause the release of proinflammatory cytokines in the blood of patients, such as IL-1b and TNF-a (39), and the release of ROS, cTnT, and LDH, markers of cytotoxic and cardiotoxic responses (1,(40)(41)(42). In the heart, inflammation is stimulated by Doxo-induced cell apoptosis and tissue damage; this effect involves the activation of the TNF signaling pathway, the generation of massive ROS, and the persistent expression of multiple proinflammatory cytokines such as IL-1b and TNF-a (39,55,56). Thus, the heart itself can be an important source of inflammatory and damage markers.…”

Section: Discussionmentioning

confidence: 99%

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

et al. 2019

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The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose‐dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full‐length recombinant CgA on Doxo‐induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo‐induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury. On the other hand, CgA did not impair the anticancer activity of Doxo in all the murine models investigated. Furthermore, we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low‐dose CgA to patients with low levels of endogenous CgA might represent a novel approach to prevent Doxo‐induced adverse events without impairing antitumor effects.—Rocca, C., Scavello, F., Colombo, B., Gasparri, A. M., Dallatomasina, A., Granieri, M. C., Amelio, D., Pasqua, T., Cerra, M. C., Tota, B., Corti, A., Angelone, T. Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity. FASEB J. 33, 7734–7747 (2019). http://www.fasebj.org

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“…A total of 24 healthy male Wistar rats, weighting 250 ± 10 g, obtained from Department of Laboratory Animal Science of China Medical University were divided into two groups (n = 12): (I) the rats were administrated by a single tail‐vein injection of 15 μL PBS diluting 5 × 10 10 particles of adeno‐associated virus (AAV) delivering small hairpin RNAs (shRNAs) generated by Hanbio (Shanghai, China)per rat as previously described and(II) the rats were given the same dose of scrambled shRNA(Shanghai, China) as control. Four weeks after the injection, the expression of GAS5 in left ventricular myocardium was determined using qRT‐PCR to examine the down‐regulation of GAS5.…”

Section: Methodsmentioning

confidence: 99%

Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

Zhang

Bao

et al. 2019

J Cellular Molecular Medi

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Growth arrest‐specific transcript 5 (GAS5), along non‐coding RNA (LncRNA), is highly expressed in hypoxia/reoxygenation (H/R)‐cardiomyocytes and promotes H/R‐induced apoptosis. In this study, we determined whether down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion (I/R) injury and further explored its mechanism. GAS5 expression in cardiomyocytes and rats was knockdown by transfected or injected with GAS5‐specific small interfering RNA or adeno‐associated virus delivering small hairpin RNAs, respectively. The effects of GAS5 knockdown on myocardial I/R injury were detected by CCK‐8, myocardial enzyme test, flow cytometry, TTC and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. qRT‐PCR and luciferase reporter assay were carried out to analyse the relationship between GAS5 and miR‐335. The regulation of GAS5 on Rho‐associated protein kinase 1 (ROCK1) expression, the activation of PI3K/AKT/GSK‐3β pathway and mitochondrial permeability transition pore (mPTP) opening was further evaluated. The results indicated that GAS5 knockdown enhanced the viability, decreased apoptosis and reduced the levels of lactate dehydrogenase and creatine kinase‐MB in H/R‐treatment cardiomyocytes. Meanwhile, down‐regulation of GAS5 limited myocardial infarct size and reduced apoptosis in I/R‐heart. GAS5 was found to bind to miR‐335 and displayed a reciprocal inhibition between them. Furthermore, GAS5 knockdown repressed ROCK1 expression, activated PI3K/AKT, thereby leading to inhibition of GSK‐3β and mPTP opening. These suppressions were abrogated by miR‐335 inhibitor treatment. Taken together, our results demonstrated that down‐regulation of GAS5 ameliorates myocardial I/R injury via the miR‐335/ROCK1/AKT/GSK‐3β axis. Our findings suggested that GAS5 may be a new therapeutic target for the prevention of myocardial I/R injury.

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CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1

Cited by 128 publications

References 39 publications

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

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