1, 8-cineole protects against ISO-induced heart failure by inhibiting oxidative stress and ER stress in vitro and in vivo.

Sugemule-3 is widely adopted in clinical practice to manage cardio-cerebral diseases. 1, 8-cineole is the main ingredient of Sugemule-3, however, the underlying cellular mechanisms for its protective effect are poorly understood. 1, 8-cineole improved the survival of H9C2 cardiomyocytes during isoproterenol (ISO) injury and reduced ISO-induced apoptosis. Compared to the ISO group, 1, 8-cineole highly attenuated the generation of ISO-induced reactive oxygen species (ROS), the depolarization of △ψm, suppression of the Bax/Bcl-2 ratio, and p-caspase 3 expression, in vitro. Furthermore, 1, 8-cineole treatment in H9C2 cardiomyocytes lowered the expressions of 78-kDa glucose-regulated protein (GRP78), p-protein kinase-like ER kinase (PERK), activation of transcription factor (ATF) 4, and ER stress effector protein C/EBP and homologous protein (CHOP). These findings implied that 1, 8-cineole contribute to cardioprotection via the GRP78/CHOP pathways. Using animal models, 1, 8-cineole was revealed to markedly alleviate ISO-induced heart injury, and reduce cardiac hypertrophy, formation of the cytoplasmic vacuole, loss of myofiber, and fibrosis by inhibiting oxidative stress and ER stress. 1, 8-cineole reduces apoptosis by inhibiting signaling pathways related to oxidative stress and ER stress. These findings implicate 1, 8-cineole as a potential therapeutic target for cardiac hypertrophy-related heart diseases, including heart failure.