Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca2+ homeostasis

Background We have previously shown that Elatoside C reduces cardiomyocyte apoptosis during ischaemia/reperfusion (I/R). Here, we investigated whether Elatoside C improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in Elatoside C-induced protection. Methods and results Isolated rat hearts were subjected to global ischaemia followed by reperfusion in the absence or presence of Elatoside C. We found that Elatoside C significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Consistently, Elatoside C prevented I/R-induced mitochondrial dysfunction, which was evident by the inhibition of mitochondrial ROS production, mitochondrial permeability transition pore (mPTP) opening, cytochrome c release from the mitochondria and Bax translocation. Moreover, Elatoside C improved abnormal calcium handling during I/R, including increasing sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activity, alleviating [Ca2+]ER depletion, and reducing the expression levels of ER stress protein markers. All of these protective effects of Elatoside C were partially abolished by the PI3K/Akt inhibitor LY294002, ERK1/2 inhibitor PD98059, and JAK2/STAT3 inhibitor AG490. Further assessment in isolated cardiomyocytes showed that Elatoside C maintained the Ca2+ transients and cell shortening against I/R. Conclusions Elatoside C protects against cardiac injury during I/R by attenuating oxidative stress and [Ca2+]i overload through the activation of both the reperfusion injury salvage kinase (RISK) pathway (including PI3K/Akt and ERK1/2) and the survivor activating factor enhancement (SAFE) pathway (including JAK2/STAT3) and, subsequently, inhibiting the opening of mPTPs.