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Down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 translocation and release and protects against liver ischemia-reperfusion injury

View Article: PubMed Central - PubMed

ABSTRACT

Hepatocyte-specific HMGB1 deletion has been found to worsen the injury and inflammation in liver ischemia-reperfusion injury (IRI), highlighting a role for intracellular HMGB1 in cellular protection. Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) might not only decrease its injurious extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against IRI. We established a non-lethal liver IRI model in mice via segmental hepatic warm ischemia for 1 h and reperfusion for 6 h. HMGB1-siRNA achieved a reduction of ~60–70% in the nuclear HMGB1 expression in the liver at 48 h post-treatment. Knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and of HMGB1 release after hepatic reperfusion, resulting in significant preservation of liver function and a marked reduction in pathological damage. Also, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2 seen in control mice after hepatic reperfusion. We demonstrated for the first time that down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 release and protects against liver IRI, which is helpful for better understanding the role of HMGB1 in organ IRI.

No MeSH data available.


Related in: MedlinePlus

Down-regulation of nuclear HMGB1 protects against hepatic IRI.After 60 min of hepatic warm ischemia and reperfusion, the serum ALT (A) and AST (B) levels of sham-operated (sham), PBS-treated (PBS), scrambled siRNA-treated (scramble), and HMGB1 siRNA-treated (si-HMGB1) mice at 6 h after reperfusion were measured to assess the degree of liver dysfunction (**P < 0.01, n = 9 per group).
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f2: Down-regulation of nuclear HMGB1 protects against hepatic IRI.After 60 min of hepatic warm ischemia and reperfusion, the serum ALT (A) and AST (B) levels of sham-operated (sham), PBS-treated (PBS), scrambled siRNA-treated (scramble), and HMGB1 siRNA-treated (si-HMGB1) mice at 6 h after reperfusion were measured to assess the degree of liver dysfunction (**P < 0.01, n = 9 per group).

Mentions: To determine whether gene silencing of HMGB1 could protect against liver IRI, mice were given PBS, scrambled siRNAs, or HMGB1-siRNA 48 h before ischemia, and serum ALT and AST levels were measured to assess the degree of liver dysfunction in each group. As compared to sham-operated mice, both PBS- and scrambled siRNA-treated mice exposed to 60 min of warm hepatic ischemia, followed by 6 h of reperfusion, showed markedly increased serum alanine aminotransferase (sALT) and serum aspartate transaminase (sAST) levels. In contrast, pretreatment with HMGB1-siRNA resulted in significant protection from hepatic injury, as evidenced by much lower levels of both serum ALT and AST in this group than in either the PBS- or scrambled siRNA-treated groups (p < 0.01) (Fig. 2).


Down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 translocation and release and protects against liver ischemia-reperfusion injury
Down-regulation of nuclear HMGB1 protects against hepatic IRI.After 60 min of hepatic warm ischemia and reperfusion, the serum ALT (A) and AST (B) levels of sham-operated (sham), PBS-treated (PBS), scrambled siRNA-treated (scramble), and HMGB1 siRNA-treated (si-HMGB1) mice at 6 h after reperfusion were measured to assess the degree of liver dysfunction (**P < 0.01, n = 9 per group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382773&req=5

f2: Down-regulation of nuclear HMGB1 protects against hepatic IRI.After 60 min of hepatic warm ischemia and reperfusion, the serum ALT (A) and AST (B) levels of sham-operated (sham), PBS-treated (PBS), scrambled siRNA-treated (scramble), and HMGB1 siRNA-treated (si-HMGB1) mice at 6 h after reperfusion were measured to assess the degree of liver dysfunction (**P < 0.01, n = 9 per group).
Mentions: To determine whether gene silencing of HMGB1 could protect against liver IRI, mice were given PBS, scrambled siRNAs, or HMGB1-siRNA 48 h before ischemia, and serum ALT and AST levels were measured to assess the degree of liver dysfunction in each group. As compared to sham-operated mice, both PBS- and scrambled siRNA-treated mice exposed to 60 min of warm hepatic ischemia, followed by 6 h of reperfusion, showed markedly increased serum alanine aminotransferase (sALT) and serum aspartate transaminase (sAST) levels. In contrast, pretreatment with HMGB1-siRNA resulted in significant protection from hepatic injury, as evidenced by much lower levels of both serum ALT and AST in this group than in either the PBS- or scrambled siRNA-treated groups (p < 0.01) (Fig. 2).

View Article: PubMed Central - PubMed

ABSTRACT

Hepatocyte-specific HMGB1 deletion has been found to worsen the injury and inflammation in liver ischemia-reperfusion injury (IRI), highlighting a role for intracellular HMGB1 in cellular protection. Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) might not only decrease its injurious extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against IRI. We established a non-lethal liver IRI model in mice via segmental hepatic warm ischemia for 1&thinsp;h and reperfusion for 6&thinsp;h. HMGB1-siRNA achieved a reduction of ~60&ndash;70% in the nuclear HMGB1 expression in the liver at 48&thinsp;h post-treatment. Knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and of HMGB1 release after hepatic reperfusion, resulting in significant preservation of liver function and a marked reduction in pathological damage. Also, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-&alpha;, IL-1&beta;, IL-6, MCP-1, iNOS, and COX-2 seen in control mice after hepatic reperfusion. We demonstrated for the first time that down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 release and protects against liver IRI, which is helpful for better understanding the role of HMGB1 in organ IRI.

No MeSH data available.


Related in: MedlinePlus