Salvianolic acid B attenuates doxorubicin-induced ER stress by inhibiting TRPC3 and TRPC6 mediated Ca2+ overload in rat cardiomyocytes

- Sal B pretreatment protected against DOX-induced cardiotoxicity in vitro and in vivo.
- DOX induced Ca2+ via activating TRPC3 and TRPC6.
- Sal B inhibited DOX-induced ER stress and apoptosis via suppressing TRPC3 and TRPC6 activation.

Doxorubicin (DOX)-induced cardiotoxicity is a clinically complex syndrome that leads to significant pain to cancer survivors. Endoplasmic reticulum (ER) stress has been suggested to be an important contributor to myocardium dysfunction during this phenomenon. Our previous study proved that Salvianolic acid B (Sal B) protected against doxorubicin induced cardiac dysfunction by inhibiting ER stress and cardiomyocyte apoptosis. However, the underlying molecular mechanism is not yet clearly. In this study, we investigated the protective effect and mechanisms of Sal B againest DOX-induced cardiac injury and ER stress in vivo and in vitro. After pretreatment with Sal B (0.25, 0.5, 1 mg/kg i.v.) for 7 days, male SD rats were intraperitoneally injected with a single dose of DOX (3 mg/kg) every 2 days for three injections. The cardioprotective effect of Sal B was observed 2 weeks after the first administration. Adult rat ventricular myocytes were isolated and treated with Sal B (20 μg/ml) for 6 h and then exposed in DOX (1 μm) for 4 h. The cardiomyocyte contractility and the level of intracellular Ca2+ were determined. Sal B ameliorated DOX-induced apoptosis damage in heart tissues. In vitro studies showed that DOX induced adult rat ventricular myocytes contractile dysfunction and intracellular Ca2+ handling derangement, disrupted mitochondrial membrane potential, raised the level of ER stress related proteins. However, Sal B pretreatment suppressed all of these adverse effects of DOX. The effects of Sal B were closely related to the inhibition of transient receptor potential canonical (TRPC) channels, as characterized by inhibiting the expression of TRPC 3 and TRPC6. These results indicate that Sal B protects against DOX-induced cardiac apoptosis and ER stress via TRPC3 and TRPC6 inhibition.