Modulation of the unfolded protein response during hepatocyte and cardiomyocyte apoptosis in trauma/hemorrhagic shock

Abstract

Trauma with hemorrhagic shock (T/HS), has been shown to result in liver injury marked by hepatocyte apoptosis and heart failure marked by cardiomyocyte apoptosis, both of which we have shown to be prevented by IL-6 administration at resuscitation, and Stat3 largely mediated this. As specific mediators have not been delineated, we investigated the unfolded protein response (UPR), which, with marked activation, can lead to apoptosis. Prior studies of hepatic and cardiac injury examined limited repertoires of UPR elements, making it difficult to assess the role of the UPR in T/HS. This study describes the first global examination of the UPR transcriptome in the liver and heart following T/HS, demonstrating organ-specific UPR transcriptome changes. The non-canonical UPR chaperone, Hsp70, was most dysregulated following T/HS and may contribute to hepatocyte protection via an IL-6-mediated pathway, identifying a potential new therapeutic strategy to prevent hepatocyte death and organ dysfunction in T/HS.

Figure 1. Unbiased hierarchical heatmap clustering based on both UPR entity and experimental intervention of animals confined to 113 UPR-associated gene entities on whole liver preparations.

Clustering performed using Hierarchical analysis using Euclidean similarity measure, expression data normalized to chip standards for clustering.

Figure 2. Q-RT-PCR using TaqMan® (Life Technologies) for (A) heat shock protein 70 (Hsp70; Hspa1a) and (B) heat shock protein 40 (Hsp40; Dnajb1) performed on whole liver samples from Sham (n = 6), trauma with hemorrhagic shock (T/HS, n = 4), and T/HS animals resuscitated with IL-6 (T/HS-IL6, n = 4).

Transcript values reported as relative quantification (RQ) in comparison to a normal rat liver. Values expressed as mean RQ ± SEM. “*”, “**” indicate group comparisons which are statistically different (p < 0.05) by T-test.