Comparison of exercise training and estrogen supplementation on mast cell-mediated doxorubicin-induced cardiotoxicity

Abstract

Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased β-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.

Acute and Delayed Doxorubicin-Induced Myocardiotoxicity Associated with Elevation of Cardiac Biomarkers, Depletion of Cellular Antioxidant Enzymes, and Several Histopathological and Ultrastructural Changes

“…However, the chronic phase in the present study showed a significant increase of cardiac biomarkers in comparison with the group-specific control, suggesting that mitochondrial redox status is not the dominant factor contributing to the observed mitochondrial damage. Interestingly, we noticed the presence of degranulated mast cells in the heart of chronic group, which aggravate the possible role of the bioactivated components of DOX [ 73 ].…”

Exercise to Reduce Anthracycline-Mediated Cardiovascular Complications in Breast Cancer Survivors

“…The reductions in these pro-apoptotic markers indicate exercise can decrease cardiomyocyte apoptosis in the setting of DOX leading to preserved heart structure and function. Important to note, these studies showed similar results in reducing pro-apoptotic markers despite the length of the training program, which varied from as short as 2 weeks to as long as 14 weeks [34,36,38].…”

“…They found that exercise training was able to attenuate DOX-induced increases in pro-apoptotic proteins including Bax and cleaved caspase 3 [36]. The ability of AE to attenuate cleaved caspase 3 activity has also been observed in other chronic exercise studies [34,38]. The reductions in these pro-apoptotic markers indicate exercise can decrease cardiomyocyte apoptosis in the setting of DOX leading to preserved heart structure and function.…”

“…This was also corroborated by chronic exercise studies which found attenuated levels of myocardial lipid peroxidation in rats that ran on treadmills or wheels prior to DOX treatment compared to their sedentary counterparts [31][32][33]. Most recently, Phungphong et al showed a 10-week exercise program led to the attenuation of DOX-induced increases in serum protein carbonylation, a marker of oxidative stress [34].…”

Consideration of Sex as a Biological Variable in the Development of Doxorubicin Myotoxicity and the Efficacy of Exercise as a Therapeutic Intervention

“…These actions may explain why ovariectomized (OVX) rodents exhibit exacerbated DOX cardiotoxicity compared to DOX-treated cycling females [44]. Further supporting the protective role of estrogen in DOX cardiotoxicity are data showing the attenuation of DOX cardiac effects in OVX rodents following supplementation with estrogen [48,123]. The role of testosterone in DOX-induced cardiotoxicity, however, remains unclear, with studies suggesting exacerbated cardiotoxicity [94], no change in cardiac function [48], or attenuation of DOXinduced senescence [124] and oxidative stress [125].…”