Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats

Arafa, Manar Hamed; Mohammad, Nanies Sameeh; Atteia, Hebatallah Husseini; Abdel-Aziz, Hesham R.

doi:10.1007/s13105-014-0339-y

Cited by 108 publications

(83 citation statements)

References 45 publications

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“…Here, we found a marked reduction in left ventricular end-diastolic posterior wall thickness, ejection fraction, and fractional shortening percentage in Dox-treated rats, concomitantly with increased cardiomyocyte membrane permeability and serum LDH concentration. This was consistent with previous studies in several animal models [8,19,33]. However, upregulation of miR-29b was effective in improving cardiac function.…”

Section: Discussionsupporting

confidence: 93%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

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Section: Discussionsupporting

confidence: 93%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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“…Therefore, upregulating the mRNA level of TIMPs or downregulating the mRNA levels of TGFβ-1 and MMPs may inhibit fibrosis. Fibrosis is reportedly induced by ADR in myocardial tissue (31), which is supported by the present study findings. The present results indicate that EP can alleviate ADR-induced fibrosis by upregulating the mRNA levels of MMPs relative to those of TIMPs as well as downregulating the mRNA levels of TGFβ-1 and TIMPs, since it was observed that rats in the ADR + EP group had a lower collagen volume fraction in myocardial tissue, lower mRNA levels of TGFβ-1, TIMP1, TIMP2, Colla1 and Colla3, and higher ratios of MMP9/TIMP1 and MMP2/TIMP2, compared with those in the ADR group.…”

Section: Discussionsupporting

confidence: 92%

Impact of ethyl pyruvate on Adriamycin-induced cardiomyopathy in rats

Liu

Wang

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Ethyl pyruvate (EP), a derivative of pyruvic acid, is known to have protective effects against ischemic cardiomyopathy and other disorders. However, little is known about its role in Adriamycin (ADR)-induced cardiomyopathy. The present study was designed to investigate the impact of EP on ADR-induced cardiomyopathy in an animal model. Sixty male Sprague-Dawley (SD) rats were divided into four groups: Normal control, EP, ADR and ADR + EP groups (n=15/group). Rats in the ADR and ADR + EP groups were treated with ADR (2.5 mg/kg/week intraperitoneally) for 6 weeks. From the eighth week, rats in the EP and ADR + EP groups received EP via gastric lavage at a dose of 50 mg/kg/day for 30 days. After completing the EP treatment, cardiac function was assessed by echocardiography and then rats were sacrificed. Hearts were harvested for subsequent analysis. Compared with rats in the normal control and EP groups (without ADR treatment), rats in the ADR and ADR + EP groups showed significant impairments in terms of cardiac function, apoptosis, severe oxidative stress and fibrosis in the heart. However, these impairments were alleviated by EP treatment in the ADR + EP group. Upon EP treatment, cardiac function was significantly improved. The levels of oxidative stress, fibrosis and apoptosis in the myocardial tissues were also significantly reduced. These findings indicated that EP treatment attenuated, at least partially, ADR-induced cardiomyopathy in rats.

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“…doxorubicin, sunitinib, cisplatin, and trastuzumab) have been demonstrated to cause severe acute and chronic cardiotoxic effects that may lead to cardiac dysfunction and heart failure [202,203]. A number of studies have demonstrated that resveratrol protects against doxorubicin-induced cardiotoxicity in a variety of animal models (Table 5) [261][262][263][264][265][266]. Multiple mechanisms have also been proposed to explain the protective effect of resveratrol against doxorubicin-induced cardiotoxicity.…”

Section: Chemotherapy-induced Cardiotoxicitymentioning

confidence: 99%

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

Zordoky

Robertson

Dyck

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

288

217

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Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

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Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats

Cited by 108 publications

References 45 publications

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Impact of ethyl pyruvate on Adriamycin-induced cardiomyopathy in rats

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

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