Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity

Hullin, Roger; Métrich, Mélanie; Sarre, Alexandre; Basquin, Denis; Maillard, Marc; Regamey, Julien; Martin, David

doi:10.1093/cvr/cvx162

Cited by 63 publications

(44 citation statements)

References 33 publications

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“…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. Interestingly, the combined application of our study drugs did not result in any significant improvement in the DOX-induced overall increase in fibrosis, regardless of the time span of the treatment.…”

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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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: 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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“…For cardiotropic expression, male mice (age: 8-10 weeks; 25-30 g) received 1 × 10 11 viral genome of AAV9-miR-200a or AAV9-miR-scramble by tail vein injection according to a previous study [17]. Four weeks later, male C57BL/6J mice received a single intraperitoneal injection of DOX-HCl (Adriamycin, Sigma-Aldrich, St. Louis, MO, USA) at 15 mg/kg to mimic acute DOX exposure according to a previous study [18]. Control mice were treated with the same volume of normal saline (NS), which was used to dissolve DOX.…”

Section: Methodsmentioning

confidence: 99%

miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice

Liu

Wang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was closely involved in doxorubicin- (DOX-) induced cardiotoxicity. MicroRNA-200a (miR-200a) could target Keap1 mRNA and promote degradation of Keap1 mRNA, resulting in Nrf2 activation. However, the role of miR-200a in DOX-related cardiotoxicity remained unclear. Our study is aimed at investigating the effect of miR-200a on DOX-induced cardiotoxicity in mice. For cardiotropic expression, male mice received an injection of an adeno-associated virus 9 (AAV9) system carrying miR-200a or miR-scramble. Four weeks later, mice received a single intraperitoneal injection of DOX at 15 mg/kg. In our study, we found that miR-200a mRNA was the only microRNA that was significantly decreased in DOX-treated mice and H9c2 cells. miR-200a supplementation blocked whole-body wasting and heart atrophy caused by acute DOX injection, decreased the levels of cardiac troponin I and the N-terminal probrain natriuretic peptide, and improved cardiac and adult cardiomyocyte contractile function. Moreover, miR-200a reduced oxidative stress and cardiac apoptosis without affecting matrix metalloproteinase and inflammatory factors in mice with acute DOX injection. miR-200a also attenuated DOX-induced oxidative injury and cell loss in vitro. As expected, we found that miR-200a activated Nrf2 and Nrf2 deficiency abolished the protection provided by miR-200a supplementation in mice. miR-200a also provided cardiac benefits in a chronic model of DOX-induced cardiotoxicity. In conclusion, miR-200a protected against DOX-induced cardiotoxicity via activation of the Nrf2 signaling pathway. Our data suggest that miR-200a may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

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“…Body weight was measured twice a week. There is no literature showing the usage of sub dermic pellets of eplerenone in rodents, the choice of our dosage was similar than those chosen on previous studies where the eplerenone was added to chow (200 mg/kg pellet) (17,35,36). In our opinion the advantage of using pellets is that they deliver a constant and known dose of the drug Eplerenone to all animals regardless of the amount of food that each animal consumes.…”

Section: Animal Maintenance and Experimental Designmentioning

confidence: 99%

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division

et al. 2020

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Introduction: Mineralocorticoid receptor (MR) activation within adipose tissue, triggers inflammation and metabolic syndrome development. The pharmacological blockade of MR provides beneficial effects for adipose tissue. Our study evaluates the impact of eplerenone implantation upon obesity. Experimental approach: A group of mice with implanted placebo pellets were fed using two types of diet, a normal (ND) or a high fat (HFD) diet. Additionally, a group of mice fed HFD were implanted with an eplerenone pellet. Metabolic and biochemical parameters were assessed in each animal group. Adipocyte size and lipid accumulation were investigated in the liver and adipose tissue. We evaluated the components of renin-angiotensin-aldosterone system (RAAS) locally in adipose tissue. Key results: Eplerenone reduced HFD-induced body weight gain, fasting glucose levels, fat accumulation, HFD-induced adipocyte size and liver lipid accumulation and improved glucose tolerance. In the adipose tissue, HFD significantly increased the mRNA levels of the RAAS molecules relative to the ND group. Eplerenone lowered RAAS mRNA levels, components of lipid metabolism and markers of inflammation in HFD-fed animals. Conclusion: MR antagonism with eplerenone diminishes insulin resistance that is related to obesity partly via a reduction of RAAS activation, inflammatory progression and cytokines induction. This suggests that eplerenone should be further studied as a therapeutic option for obesity and overweight.

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Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity

Cited by 63 publications

References 33 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

miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division

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