Chemical chaperones improve the functional recovery of stunned myocardium by attenuating the endoplasmic reticulum stress

SILVESTRI, MARÍA AGUSTINA; SAID, MATILDE; ROMÁN, BÁRBARA; VITTONE, LETICIA; MARIÁNGELO, JUAN IGNACIO ELIO; SALAS, MARGARITA; MUNDIÑA-WEILENMANN, CECILIA

ACTA PHYSIOLOGICA

WILEY-BLACKWELL PUBLISHING, INC

Año: 2019

1748-1708

AimMyocardial ischemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischemia. Brief ischemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long-lasting ischemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury, however there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post-ischemic cardiac performance of the stunned heart.MethodsPerfused rat hearts were subjected to 20 min of ischemia followed by 30 min of reperfusion. UPR markers were evaluated by qRT-PCR and Western blot. Post-ischemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA).ResultsAnalysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signaling cascades, involving both pro-survival and pro-apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post-ischemic recovery of cardiac mechanical function without affecting the I/R-induced increase in oxidative stress.ConclusionOur results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.