Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
Am J Physiol Regul Integr Comp Physiol. 2020 May 1;318(5):R829-R842. doi: 10.1152/ajpregu.00224.2019. Epub 2020 Mar 11.
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 Ca 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.
心脏炎症被认为是蒽环类抗生素引起的急性心脏毒性的主要机制之一。减少心脏炎症也可能减轻心脏毒性。本研究旨在评估雌激素治疗和常规运动在蒽环类抗生素诱导的心肌病背景下减轻心脏炎症的潜力。去卵巢大鼠被随机分为雌激素补充组、运动训练组和肥大细胞稳定剂治疗组。去卵巢 8 周后，大鼠接受 6 次累积剂量的蒽环类药物治疗 2 周。超声心动图显示，蒽环类药物治疗组的射血分数逐渐下降，但没有肥厚作用。这种收缩功能缺陷完全被雌激素补充或肥大细胞稳定剂治疗所预防，但不被常规运动所预防。作为心脏病的一个指标，蒽环类药物诱导的β-肌球蛋白重链表达增加只能通过雌激素补充来预防。心肌细胞缩短和细胞内 Ca 瞬变的减少是由于缺乏雌性激素，而没有进一步的蒽环类药物作用。同样，雌激素补充和肥大细胞稳定剂治疗预防了这些变化，但运动训练没有。组织学分析表明，去卵巢大鼠心脏肥大细胞的过度激活在蒽环类药物作用下增强。雌激素补充和肥大细胞稳定剂治疗完全预防了肥大细胞密度和脱颗粒的增加，而运动训练则部分减轻了肥大细胞的过度激活。因此，我们的结果表明，雌激素补充与肥大细胞稳定剂在减轻蒽环类药物的作用方面相似。常规运动预防蒽环类药物急性心脏毒性的无效可能是由于其对预防心脏炎症的作用较小。
