Aerobic Exercise Attenuates Doxorubicin-Induced Cardiomyopathy by Suppressing NLRP3 Inflammasome Activation in a Rat Model

Abstract

Doxorubicin (DOX) is a potent chemotherapeutic agent with well-documented dose-dependent cardiotoxicity. Regular exercise is recognized for its cardioprotective effects against DOX-induced cardiac inflammation, although the precise mechanisms remain incompletely understood. The activation of inflammasomes has been implicated in the pathogenesis and treatment of DOX-induced cardiotoxicity, with the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome emerging as a key mediator in cardiovascular inflammation. This study aimed to investigate the role of exercise in modulating the NLRP3 inflammasome to protect against DOX-induced cardiac inflammation. Male Sprague–Dawley rats were randomly assigned to receive a 10-day course of DOX or saline injections, with or without a preceding 10-week treadmill running regimen. Cardiovascular function and histological changes were subsequently evaluated. DOX-induced cardiotoxicity was characterized by cardiac atrophy, systolic dysfunction, and hypotension, alongside activation of the NLRP3 inflammasome. Our findings revealed that regular exercise preserved cardiac mass and hypertrophic indices and prevented DOX-induced cardiac dysfunction, although it did not fully preserve blood pressure. These results underscore the significant cardioprotective effects of exercise against DOX-induced cardiotoxicity. While regular exercise did not entirely prevent DOX-induced hypotension, our findings demonstrate that it confers protection against DOX-induced cardiotoxicity by suppressing NLRP3 inflammasome activation in the heart, underscoring its anti-inflammatory role. Further research should explore the temporal dynamics and interactions among exercise, pyroptosis, and other pathways in DOX-induced cardiotoxicity to enhance translational applications in cardiovascular medicine.