Exercise-preconditioning attenuates TAC-induced cardiac hypertrophy and myocardial injury through activating NRF2.

Exercise protects against pathological cardiac hypertrophy and heart failure, yet the mechanisms remain unclear. We applied the established transverse aortic constriction (TAC) mouse model to induce pressure overload and heart failure, and found that exercise prior to the operation significantly attenuated TAC-induced cardiac hypertrophy, fibrosis, and systolic dysfunction. Notably, these reduction are strongly associated with activation of SIRT1-NRF2 pathway and improved oxidative stress which is robustly elevated in the control sedentary TAC mice. To confirm that cardiac protective effect of exercise relies on Nrf2 activation, we further applied the same exercise-preconditioning and TAC operation to Nrf2 knockout (Nrf2-KO) mice. NRF2 deficiency completely abolished the protective effects of the exercise: the exercise-triggered improvements in TAC-induced cardiac hypertrophy, fibrosis, systolic dysfunction, as well as oxidative stress, were all eliminated in Nrf2-KO mouse model. We conclude that exercise preconditioning confers cardioprotection primarily through Nrf2 activation, which suppresses oxidative stress and thereby attenuates pressure overload-induced cardiac hypertrophy and dysfunction.