CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Unfolded protein response in stunned heart
Autor/es:
MARIÁNGELO, J.I.E.; SALAS MA; MUNDIÑA-WEILENMANN C;; ROMAN B; SAID M; SILVESTRI MA; VITTONE L.
Lugar:
New London
Reunión:
Conferencia; Gordon Research Conference; 2018
Institución organizadora:
Gordon Research Seminar
Resumen:
Restoration of coronary flow after an ischemic event is mandatory in order to preserve cardiac function. However reperfusion itself may result in mechanical, electrical and/or viability alterations in excess to that produced by ischemia alone. The resulting tissue damage is named ischemia?reperfusion (I/R) injury and depends mainly on the duration of the ischemia. If the ischemic period is brief, I/R can cause reversible contractile dysfunction and arrhythmias (I/Rrev, stunned heart) and in its severest form (prolonged ischemia) I/R can lead to cell death (I/Rirrev). It has been demonstrated that I/Rirrev challenges the endoplasmic reticulum (ER) protein folding capacity, leading to ER stress. The cell response to ER stress is known as the unfolded protein response (UPR) and comprises three pathways which initiate both, adaptive and apoptotic signaling cascades: 1) ATF6 induces the transcription of XBP1 and GRP78 (the main ER chaperone); 2) IRE1a produces the splicing of XBP1 (sXBP1) which increases GRP78 expression and also leads to apoptosis via the activation of JNK and caspase-12 and 3) PERK attenuates protein synthesis via the phosphorylation of eIF2a and promotes the expression of the pro-apoptotic protein CHOP. There is consensus that under mild or moderate stress, upregulation of ER chaperones restores ER homeostasis and enhances survival. If the adaptive mechanisms of the UPR are not sufficient (prolonged or overwhelming protein folding stress) a switch to pro-apoptotic signals generates cell death contributing to the progression of the ischemic heart disease. 1)Study if UPR is triggered in the stunned heart (I/Rrev) and 2) compare this response with the UPR associated to an irreversible I/R damage with cell death (I/Rirrev). To do that, we work with isolated perfused hearts form Wistar male rats, subjected to two different protocols: 20 min of ischemia followed by 30 min of reperfusion (stunned heart, or reversible I/R), and 30 min of ischemia followed by 60 min of reperfusion (irreversible I/R). To characterize the UPR response, mRNA expression of GRP78, total XBP1, sXBP1 and CHOP were evaluated by real time qRT-PCR We found that GRP78, sXBP1 and total-XBP1 mRNA levels significantly increased with respect to Ctrl indicating the activation of the adaptive UPR for cell survival. In contrast, CHOP mRNA, a major pro-apoptotic signal, showed no change in I/Rrev, but increased in I/Rirrev. In order to dissect whether reperfusion length determines the activation of apoptotic signals, a group of hearts were submitted to I/R 20/60 min. Prolonging the reperfusion time did not modify the stunned heart-induced increase in mRNA levels (of GRP78 and sXBP1 and CHOP). Thus the intensity of the ischemic insult determines the outcome of the ER-induced pattern of mRNA expression.