Molecular Mechanisms Leading to Neuroprotection/Ischemic Tolerance: Effect of Preconditioning on the Stress Reaction of Endoplasmic Reticulum

Abstract

Ischemic tolerance can be developed by prior ischemic non-injurious stimulus preconditioning. The molecular mechanisms underlying ischemic tolerance are not yet fully understood. The purpose of this study is to evaluate the effect of preconditioning/preischemia on ischemic brain injury. We examined the endoplasmic reticulum stress response (unfolded protein response (UPR)) by measuring the mRNA and protein levels of specific genes such as ATF6, GRP78, and XBP1 after 15 min 4-VO ischemia and different times of reperfusion (1, 3, and 24 h). The data from the group of naïve ischemic rats were compared with data from the group of preconditioned animals. The results of the experiments showed significant changes in the gene expression at the mRNA level in the all ischemic/reperfusion phases. The influence of preischemia on protein level of XBP was significant in later ischemic times and at 3 h, the reperfusion reached 230% of the controls. The protein levels of GRP78 in preischemic animals showed a significant increase in ischemic and reperfusion times. They exceeded to 50% levels of corresponding naïve ischemic/reperfusion groups. Preconditioning also induced remarkable changes in the levels of ATF6 protein in the ischemic phase (about 170%). The levels of ATF6 remained elevated in earlier reperfusion times (37 and 62%, respectively) and persisted significantly elevated after 24 h of reperfusion. This data suggest that preconditioning paradigm (preischemia) underlies its neuroprotective effect by the attenuation of ER stress response after acute ischemic/reperfusion insult.

Biology of Endoplasmic Reticulum Stress in the Heart

“…32,58,97 A prolonged mild ischemic stimulus may lead to the cell having a tolerable amount of ER stress, thereby dictating that further insult will not significantly harm the cell by attenuation of the ER stress response after an acute ischemic episode. 98 Interestingly, overexpression of the cardiac sodium/hydrogen exchanger (NHE1) resulted in upregulation of ER stress. 99 It had been previously determined that NHE1 expression is maladaptive during cardiac function but the unexpected increase in the UPR (during NHE1 overexpression), led to enhanced survival of the mouse heart under ischemic conditions.…”

Vascular Endothelial Cell Growth–Activated XBP1 Splicing in Endothelial Cells Is Crucial for Angiogenesis

“…13,14 Several studies have shown that transient cerebral ischemia activates XBP1 mRNA splicing, which protects cell survival from ischemia/reperfusion-induced cell damage and enhances cell apoptosis. [15][16][17][18][19] Our previous study showed that XBP1 expression and splicing responded to local flow pattern and was related to EC proliferation status. 20 In the present study, we demonstrate that XBP1 mRNA splicing is involved in VEGF signaling and contributes to EC proliferation and angiogenesis in ischemic tissues.…”

Hypertension-mediated enhancement of JNK activation in association with endoplasmic reticulum stress in rat model hippocampus with cerebral ischemia-reperfusion

“…The number of dead nerve cells in the hippocampus and striatum was markedly decreased in homozygous Chop knockout mice. Lehotský et al (2009) reported that the apoptosis rate and CHOP and caspase-12 expression levels decreased while GRP78 increased at each time point in rats after a 10-min ischemia. In our experiments, GRP78 and CHOP expression levels exhibited a different time course to reach maximum levels in hypertensive rats in response to I/R.…”