RESUMEN
BACKGROUND: Doxorubicin is an effective chemotherapeutic agent, but its use is limited by acute and chronic cardiotoxicity. Exercise training has been shown to protect against doxorubicin-induced cardiotoxicity, but the involvement of immune cells remains unclear. This study aimed to investigate the role of exercise-derived B cells in protecting against doxorubicin-induced cardiotoxicity and to further determine whether B cell activation and antibody secretion play a role in this protection. METHODS: Mice that were administered with doxorubicin (5 mg/kg per week, 20 mg/kg cumulative dose) received treadmill running exercise. The adoptive transfer of exercise-derived splenic B cells to µMT-/- (B cell-deficient) mice was performed to elucidate the mechanism of B cell regulation that mediated the effect of exercise. RESULTS: Doxorubicin-administered mice that had undergone exercise training showed improved cardiac function, and low levels of cardiac apoptosis, atrophy, and fibrosis, and had reduced cardiac antibody deposition and proinflammatory responses. Similarly, B cell pharmacological and genetic depletion alleviated doxorubicin-induced cardiotoxicity, which phenocopied the protection of exercise. In vitro performed coculture experiments confirmed that exercise-derived B cells reduced cardiomyocyte apoptosis and fibroblast activation compared with control B cells. Importantly, the protective effect of exercise on B cells was confirmed by the adoptive transfer of splenic B cells from exercised donor mice to µMT-/- recipient mice. However, blockage of Fc gamma receptor IIB function using B cell transplants from exercised Fc gamma receptor IIB-/- mice abolished the protection of exercise-derived B cells against doxorubicin-induced cardiotoxicity. Mechanistically, we found that Fc gamma receptor IIB, an important B cell inhibitory receptor, responded to exercise and increased B cell activation threshold, which participated in exercise-induced protection against doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our results demonstrate that exercise training protects against doxorubicin-induced cardiotoxicity by upregulating Fc gamma receptor IIB expression in B cells, which plays an important anti-inflammatory role and participates in the protective effect of exercise against doxorubicin-induced cardiotoxicity.
Asunto(s)
Cardiotoxicidad , Miocitos Cardíacos , Ratones , Animales , Cardiotoxicidad/metabolismo , Miocitos Cardíacos/metabolismo , Doxorrubicina/toxicidad , ApoptosisRESUMEN
Recent evidences have shown that exercise training not only plays a necessary role in maintaining cardiac homeostasis, but also promotes cardiac repair after myocardial infarction. Post-myocardial infarction, exercise training has been observed to effectively increase the maximum cardiac output, and protect myocardial cells against necrosis and apoptosis, thus leading to an improved quality of life of myocardial infarction patients. In fact, exercise training has received more attention as an adjunct therapeutic strategy for both treatment and prevention of myocardial infarction. This review summarizes the experimental evidence of the effects of exercise training in ventricular remodeling after myocardial infarction, and tries to provide theoretical basis along with suitable references for the exercise prescription aimed at prevention and therapy of myocardial infarction.