Pharmacological inhibition of translocon is sufficient to alleviate endoplasmic reticulum stress and improve Ca handling and contractile recovery of stunned myocardium.

INTRODUCTION

The function of endoplasmic reticulum (ER), a Ca storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis. Misfolded proteins accumulated in the ER lead to ER stress (ERS), unfolded protein response (UPR) activation and ER Ca loss. Myocardial stunning is a temporary contractile dysfunction, which occurs after brief ischemic periods with minimal or no cell death, being oxidative stress and Ca overload potential underlying mechanisms. Myocardial stunning induces ERS response with negatively impact on the post-ischemic mechanical performance through an unknown mechanism.

AIMS

In this study, we explored whether ER Ca efflux through the translocon, a major Ca leak channel, contributes to Ca mishandling and the consequent contractile abnormalities of the stunned myocardium.

METHODS

Mechanical performance, cytosolic Ca, UPR markers and oxidative state were evaluated in perfused rat/mouse hearts subjected to a brief ischemia followed by reperfusion (I/R) in absence or presence of the translocon inhibitor, emetine (1 μM), comparing its effects with those of the chaperones TUDCA (30 μM) and 4-PBA (3 mM).

RESULTS

Emetine treatment precluded the I/R-induced increase in UPR signaling markers and improved the contractile recovery together with a remarkable attenuation in myocardial stiffness when compared to I/R hearts with no drug. This alleviation of I/R-induced mechanical abnormalities was more effective than that obtained with the chemical chaperones, TUDCA and 4-PBA. Moreover, emetine treatment produced a striking improvement in diastolic Ca handling with a partial recovery of the I/R-induced oxidative stress.

CONCLUSION

Blocking ER Ca store depletion via translocon suppressed ER stress and improved mechanical performance and diastolic Ca handling of stunned myocardium. Modulation of translocon permeability emerges as a therapeutic approach to face dysfunctional consequences of the I/R injury.