INHIBITION OF THE TRANSLOCON IS SUFFICIENT TO ALLEVIATE ENDOPLASMIC RETICULUM STRESS AND IMPROVE THE POST-ISCHEMIC RECOVERY OF THE STUNNED MYOCARDIUM.

JUAN IGNACIO ELIO MARIÁNGELO; CECILIA MUNDIÑA-WEILENMANN; LETICIA VITTONE; MATILDE SAID

Virtual

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC), SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI), SOCIEDAD ARGENTINA DE FISIOLOGÍA (SAFIS)

Inhibition of the translocon is sufficient to alleviate endoplasmic reticulum stress and improve the post-ischemic recovery of the stunned myocardium.Myocardial stunning is a temporary contractile dysfunction after the relief of a discrete ischemia. Oxidative stress and intracellular Ca2+ overload are proposed for the pathogenesis of this phenomenon. The endoplasmic reticulum (ER), involved in folding and sorting of proteins, is also a Ca2+ storage compartment sensitive to alterations in intracellular homeostasis. The perturbation in ER function leads to accumulation of misfolded proteins, ER stress, activation of the unfolded protein response (UPR) and frequently ER Ca2+ loss. In stunned hearts, the triggered ER stress impairs the post-ischemic myocardial performance. Since ER Ca2+ release could participate in the altered Ca2+ homeostasis, we explored whether the translocon, an ER Ca2+ leak channel, contributes to the contractile dysfunction.Mechanical performance, UPR markers and oxidative damage of perfused rat hearts subjected to 20 min of ischemia followed by 30 min of reperfusion in absence (I/R) or presence of the translocon inhibitor, Emetine (I/R+E,1 M) (n=4-7), were evaluated.Emetine precluded the I/R-induced increase in relative mRNA levels of two UPR signaling markers: GRP78 1.79±0.09 (I/R) vs 1.16±0.19 (I/R+E) and sXBP1 2.14±0.21 (I/R) vs 1.12±0.15 (I/R+E), P< 0.05. The contractile recovery significantly improved together with a remarkable attenuation in myocardial stiffness. At the end of reperfusion, left ventricular developed pressure values (% of pre-ischemia) were 45.63±3.16 (I/R) and 105.68±6.34 (I/R+E) while left ventricular end diastolic pressure values (mmHg) were 48.40±1.87 (I/R) and 14.89±4.81 (I/R+E). This occurred despite more severe oxidative stress conditions than that elicited by non-treated I/R hearts [TBARS (nmol/mgprot) 0.71±0.06 (I/R) vs 0.97±0.09 (I/R+E)].In conclusion, blocking ER Ca2+depletion via translocon suppressed ER stress and produced a beneficial effect on the mechanical performance of stunned myocardium even in the absence of any attenuation of oxidative stress.