STIM1 deficiency protects the liver from ischemia/reperfusion injury in mice

Jan 7, 2018Biochemical and biophysical research communications

Lack of STIM1 protein helps protect the liver from blood flow injury in mice

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Higher serum alanine aminotransferase (ALT) and aminotransferase (AST) levels were observed in wild type mice after liver ischemia reperfusion injury.

Wild type mice exhibited increased STIM1 expression in liver tissue following ischemia reperfusion injury compared to STIM1-knockout mice.
STIM1-knockout mice showed reduced liver injury, as indicated by improved pathological changes in liver sections after ischemia reperfusion.
Serum levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were significantly lower in STIM1-knockout mice after injury.
Oxidative stress markers, such as superoxide dismutase activity, malondialdehyde, and reactive oxygen species levels, were improved in STIM1-knockout mice post-injury.
Decreased levels of apoptosis-related proteins, including NFAT1, Orai1, and cleaved Caspase-3, were found in the livers of STIM1-knockout mice.

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Hepatic ischemia reperfusion (I/R) injury is unavoidable in various clinical conditions. Despite considerable investigation, the underlying molecular mechanism revealing liver I/R injury remains elusive. Stromal interaction molecule 1 (STIM1) plays essential role in regulating the induction of cellular responses to a number of stress conditions, including temperature changes, elevated ROS, and hypoxia. Here, to explore if STIM1 is involved in hepatic injury, wild type (WT) and STIM1-knockout (STIM1) mice were subjected to I/R. Our results indicated that the WT mice with hepatic I/R injury showed higher STIM1 expressions from gene and protein levels in liver tissue samples. Similar results were observed in hypoxia-exposed cells in vitro. Significantly, STIM1attenuated hepatic injury compared to the WT mice after I/R, as evidenced by the improved pathological alterations in liver sections. WT mice subjected to liver I/R showed higher serum alanine aminotransferase (ALT) and aminotransferase (AST) levels, as well as pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β, which were significantly reduced by STIM1. In addition, STIM1also decreased the liver mRNA levels of pro-inflammatory cytokines in mice after I/R injury. Furthermore, significantly decreased oxidative stress was found in STIM1mice after I/R injury compared to the WT group of mice, evidenced by the enhanced superoxide dismutase (SOD) activity and the reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels in liver tissue samples. Moreover, STIM1mice with hepatic I/R injury displayed the down-regulated nuclear factor of activated T cell (NFAT1), Orai1 and cleaved Caspase-3 levels in liver, contributing to apoptosis suppression. The results above were confirmed in hypoxia-treated cells lacking of STIM1 expression. Together, the findings suggested that STIM1-deletion protects the liver from I/R injury in mice through inhibiting inflammation, oxidative stress and apoptosis. STIM1 could be considered as a potential therapeutic target to ameliorate I/R injury. -/--/--/--/--/--/-

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STIM1 deficiency protects the liver from ischemia/reperfusion injury in mice

Abstract

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