P 114 - High cholesterol diet-mediated unfolded protein response activation enhances autophagic cell death in heart tissue

Abstract

The role of ER in the proper synthesis and correct folding of protein, to establish the homeostasis of organism, is well documented by various studies. Following excessive oxidative stress, the accumulation of unfolded/misfolded proteins increase in the lumen of ER which blocks the inhibitory effect of GRP78 on UPR regulatory proteins; IRE1, PERK and ATF6. It is clear that ER stress mediated UPR is a potent inducer of proteasomal and autophagic activities which serves as a degradation process for maintaining stress tolerance, limited damage and viability under stress conditions. Interestingly, aberrantly activation of autophagy can result in destroying major portions of the cytosol and organelles, which will lead to autophagic death of cardiac myocytes, and development of cardiac failure. In the present study Grp78, Grp94, pIRE1, pPERK, derlin-1, proteasome β5 subunit, VCP, beclin-1 and LC3-II, well known markers of ER stress, proteasomal and autophagic activities, are investigated in the heart tissue of rabbits. Furthermore, autophagic activity in heart tissue is observed in hypercholesterolemic vs control rabbits by electron microscopy. Additionally, colocalization studies of mitochondria and p62 in cryo sections of heart tissue were applied to understand the levels of mitochondria degradation by autophagy.