Spironolactone Attenuates Doxorubicin‐induced Cardiotoxicity in Rats

Liu, Guangzhong; Liu, Yongwu; Wang, Renjun; Hou, Tingting; Chen, Chaoyi; Zheng, Sijia; Dong, Zengxiang

doi:10.1111/1755-5922.12189

Cited by 34 publications

(31 citation statements)

References 24 publications

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“…TUNEL) detecting DNA damage and fragmentation. Previously, many research groups examined the preventability of DNA damage in experimental DOX cardiomyopathy [7, 59, 63]. In accordance with their results, we successfully demonstrated that both the prophylactic and the conventionally scheduled therapy significantly reduce the degree of DNA fragmentation captured by TUNEL.…”

Section: Discussionsupporting

confidence: 81%

“…Fibrosis represents another domain of DOX cardiomyopathy, which is also the subject of intensive preclinical research. Carvedilol [7], captopril [16], telmisartan [16] and spironolactone [63] have all been found to decrease DOX-induced myocardial fibrosis in small animals. Despite this, studies examining eplerenone gave either negative [12] or inconclusive results [13] when tested for the reversibility of DOX-induced interstitial fibrosis in mice.…”

Section: Discussionmentioning

confidence: 99%

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Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

et al. 2019

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Background Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. Methods Male Wistar rats ( n = 7–11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. Results The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. Conclusion For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment. Electronic supplementary material The online version of this article (10.1186/s12967-019-1978-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

et al. 2019

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“…In addition, it has been revealed that the expression of TGF-β1 was increased in the DOX-treated hearts [37]. Approaches that were used to reduce TGF-β1 also resulted in lower interstitial and perivascular fibrosis, along with less left ventricular dysfunction [38]. It has been revealed that mitochondrial reactive oxygen species-induced ERK1/2 activation was required for DOX-induced apoptosis and cardiotoxicity [39].…”

Section: Discussionmentioning

confidence: 99%

Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-caused Cardiac Dysfunction through Inhibition of Cardiac Fibrosis and Inflammation

Yang

Hsieh

Hung

et al. 2020

Cancers

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Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of IκBα, NF-κB, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-β1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.

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“…The exact molecular mechanisms underlying DOX-induced cardiotoxicity are complex and still not fully clarified. Studies have proposed that oxidative stress, inflammation, and apoptosis are the main players that control DOX pathogenesis 6. Excessive generation of free radicals during DOX metabolism augments oxidative stress, lipid peroxidation, membrane damage, and cardiomyocyte death 1.…”

Section: Introductionmentioning

confidence: 99%

Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways

El‐Agamy

El-Harbi

Khoshhal

et al. 2018

CMAR

100

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Background/purposePristimerin (Pris) is triterpenoid compound with many biological effects. Until now, nothing is known about its effect on doxorubicin (DOX)-induced cardiotoxicity. Hence, this study investigated the impact of Pris on DOX-induced cardiotoxic effects.Materials and methodsRats were treated with Pris 1 week before and 2 weeks contaminant with repeated DOX injection. Afterwards, electrocardiography (ECG), biochemical, histopathological, PCR, and Western blot assessments were performed.ResultsPris effectively alleviated DOX-induced deleterious cardiac damage. It inhibited DOX-induced ECG abnormities as well as DOX-induced elevation of serum indices of cardiotoxicity. The histopathological cardiac lesions and fibrosis were remarkably improved in Pris-treated animals. Pris reduced hydroxyproline content and attenuated the mRNA and protein expression of the pro-fibrogenic genes. The antioxidant activity of Pris was prominent through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, Pris enhanced the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway as it increased the mRNA and protein expression of Nrf2 and Nrf2-dependent antioxidant genes (GCL, NQO1, HO-1). Additionally, the anti-inflammatory effect of Pris was obvious through the inhibition of mitogen activated protein kinase (MAPK)/nuclear factor kappa-B (NF-kB) signaling and subsequent inhibition of inflammatory mediators.ConclusionThis study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways.

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Spironolactone Attenuates Doxorubicin‐induced Cardiotoxicity in Rats

Abstract: This study show that SP may have a protective effect on DOX-induced cardiotoxicity.

Cited by 34 publications

References 24 publications

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-caused Cardiac Dysfunction through Inhibition of Cardiac Fibrosis and Inflammation

Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways

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