The role of molecular chaperonins in warm ischemia and reperfusion injury in the steatotic liver: A proteomic study

Abstract

BackgroundThe molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software.ResultsThe relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1was significantly upregulated in steatotic liver following I/R.ConclusionDown-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts.

Human heat shock protein 27 exacerbates ischemia reperfusion injury in rats by reducing the number of T regulatory cells

“…In addition to the regular function of HSP in folding and unfolding proteins, induction of its expression in response to stress has been suggested to be protective for the cells (18,19). A proteomic analysis showed that the blockage of chaperones such as HSP may contribute to increased rates of apoptosis and necrosis (20). Hence, we investigated the roles of HSP in response to hepatocyte injury.…”

Proteomics in Liver Transplantation: A Systematic Review

“…Three other studies recollected both ischemia and reperfusion samples and compared them to control (pre- ischemia) samples and even between them (18,29,36). When rats were used as a model, Knecht et al (16) carried out ex vivo cold storage and normothermic reperfusion, whereas the other 2 publications performed a model of in vivo selective warm ischemia using vascular clamping followed by reperfusion, such in normal (20) as in steatotic rats (27).…”

Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis

“…Tiriveedhi et al have demonstrated that even the proteome profiles of livers with steatosis subjected to IRI, are significantly different compared to lean livers (23).…”

“…by Tiriveedhi et al has shown significant down-regulation of multiple chaperones upon IRI in steatotic liver, which may contribute to the augmented levels of ER stress and, subsequently, in apoptosis and necrosis observed in livers with steatosis, in contrast to lean ones(78). However, Henkel et al, have shown that chemical chaperones inhibit the ER stress response without reducing hepatic steatosis in MCD diet-fed mice(76).Selectins.…”