Ca2+ efflux through the translocon contributes to endoplasmic reticulum stress (ER) and Ca 2+ mishandling in stunned myocardium.

MARIÁNGELO, JUAN I.E.; VALVERDE CA; VITTONE L.; SAID M; MUNDIÑA - WEILENMANN C

Congreso; Reunión conjunta de la Sociedad Argentina de Fisiología (SAFIS) y la Asociación Latinoamericana de Ciencias Fisiológicas (ALACF),; 2021

SAIC, ALALCF

Aims: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis. Misfolded proteins accumulated in the ER lead to ER stress, unfolded protein response (UPR) activation and ER Ca2+ loss. ER stress is present in myocardial stunning, a temporary contractile dysfunction occurring after brief periods of ischemia which is proposed to be triggered by oxidative stress and Ca2+ overload. We explored whether ER Ca2+ efflux through the translocon, a major Ca2+ leak channel activated during ER stress, 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 rat/mouse hearts subjected to a brief ischemia followed by reperfusion in absence (I/R) or presence of the translocon inhibitor, emetine (I/R+E, 1 M). 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-eIF2. 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