Opening of the translocon during ER stress participates in the cytosolic Ca2+ overload upon reperfusion in the stunned heart.

MARIANGELO JIE; VALVERDE CA; VITTONE L; SAID M; MUNDIÑA - WEILENMANN C

Río de Janeiro

Congreso; Reunion de la International Society for Heart Research Latinoamerican Section (ISHR-LAT); 2021

International Society for Heart Research Latinoamerican Section (ISHR-LAT)

Introduction: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis, such as that occurring during myocardial stunning. Misfolded proteins accumulated in the ER lead to ER stress and unfolded protein response (UPR) activation. In stunned hearts, ER stress contributes to the post-ischemic mechanical dysfunction. Since minimal or no cell death is detected under this condition, an ER stress deleterious mechanism, other than UPR-induced apoptosis, should be participating. The translocon, a protein complex of the ER membrane involved in the transport of nascent peptides into the ER lumen, could function as a Ca2+ leak channel under ER stress. Objectives: We explored whether ER Ca2+ efflux through the translocon, contributes to Ca2+ mishandling and the consequent contractile abnormalities of the stunned myocardium.Methods: Mechanical performance, cytosolic Ca2+, UPR markers and oxidative state were evaluated in perfused male rat/mouse (300-400/25-30 gr of body weight), approval code for animal protocols (CICUAL) T05022014. Hearts subjected to a brief ischemia followed by reperfusion in absence (I/R) or presence of the translocon inhibitor, emetine (I/R+E, 1 uM). Data are expressed as mean ± SEM. Statistical significance was determined by Student?s test and ANOVA, as appropriate.Results: Emetine precluded the I/R-induced increase levels of three UPR signaling markers: GRP78, sXBP1 and phospho-eIF2a. Translocon inhibition improved the post-ischemic contractile recovery together with a remarkable attenuation in myocardial stiffness when compared to I/R without treatment (+dp/dt I/R 1187.7±124.7 vs I/R+E 2704.2±321.0 mmHg/sec; LVEDP I/R 48.4±1.87 vs I/R+E 17.63±5.66 mmHg, p