Abstract
Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP −/− animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser153 through Prostaglandin E1 or on Ser235 through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies.
Highlights
Surgical procedures such as liver transplantation, partial hepatic resection, hepatic tumor surgery or trauma repair may induce hepatic ischemia-reperfusion (IR) injury which is associated with clinically significant reduced liver function [1]
Following this VASP2/2 mice demonstrated a significant reduction of lactate dehydrogenase (LDH), AST and ALT serum levels compared to controls (Figure 1 A, B and C)
As an extension of our previous work we demonstrate here that hepatic IR injury is significantly influenced through vasodilator-stimulated phosphoprotein (VASP) expression and VASP phosphorylation
Summary
Surgical procedures such as liver transplantation, partial hepatic resection, hepatic tumor surgery or trauma repair may induce hepatic ischemia-reperfusion (IR) injury which is associated with clinically significant reduced liver function [1]. Triggered by inflammatory mediators (e.g. cytokines) neutrophils are activated to cross the endothelial barrier and translocate into hepatic tissue. This results in the release of enzymes and reactive oxygen species that aggravate the associated tissue injury within the hepatic tissue [3,4,5]. Previous work has implicated a hepatoprotective potential of PGE1 in cirrhotic patients and in experimental in vivo studies This hepatoprotective potential was described for ANP with a reduction of hepatic apoptosis and tissue injury through an ANP infusion during hepatic reperfusion [13,14,15,16]
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