Pharmacological inhibition of translocon is sufficient to alleviate endoplasmic reticulum stress and improve Ca2+ handling and contractile recovery of stunned myocardium

MARIÁNGELO, JUAN IGNACIO ELIO; VALVERDE, CARLOS ALFREDO; VITTONE, LETICIA; SAID, MATILDE; MUNDIÑA - WEILENMANN, CECILIA

EUROPEAN JOURNAL OF PHARMACOLOGY

ELSEVIER SCIENCE BV

Año: 2021

0014-2999

Introduction: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site ofprotein folding, is altered by disruption of intracellular homeostasis. Misfolded proteinsaccumulated in the ER lead to ER stress (ERS), unfolded protein response (UPR) activation and ERCa2+ loss. Myocardial stunning is a temporary contractile dysfunction, which occurs after briefischemic periods with minimal or no cell death, being oxidative stress and Ca2+ overload potentialunderlying mechanisms. Myocardial stunning induces ERS response with negatively impact on thepost-ischemic mechanical performance through an unknown mechanism.Aims: In this study, we explored whether ER Ca2+ efflux through the translocon, a major Ca2+ leakchannel, contributes to Ca2+ mishandling and the consequent contractile abnormalities of thestunned myocardium.Methods: Mechanical performance, cytosolic Ca2+, UPR markers and oxidative state wereevaluated 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 withthose of the chaperones TUDCA (30 μM) and 4-PBA (3 mM).Results: Emetine treatment precluded the I/R-induced increase in UPR signaling markers andimproved the contractile recovery together with a remarkable attenuation in myocardial stiffnesswhen compared to I/R hearts with no drug. This alleviation of I/R-induced mechanicalabnormalities was more effective than that obtained with the chemical chaperones, TUDCA and 4-PBA. Moreover, emetine treatment produced a striking improvement in diastolic Ca2+ handlingwith a partial recovery of the I/R-induced oxidative stress.Conclusion: Blocking ER Ca2+ store depletion via translocon suppressed ER stress and improvedmechanical performance and diastolic Ca2+ handling of stunned myocardium. Modulation oftranslocon permeability emerges as a therapeutic approach to face dysfunctional consequences of the I/R injury.