Phosphorylation of Vasodilator-Stimulated Phosphoprotein (VASP) Dampens Hepatic Ischemia-Reperfusion Injury

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.

现有研究已证实，血小板中性粒细胞复合物（platelet neutrophil complexes, PNCs）的形成可影响炎症性组织损伤。血管扩张剂刺激磷蛋白（Vasodilator-stimulated phosphoprotein, VASP）在调控血小板中性粒细胞复合物形成与心肌再灌注损伤过程中发挥关键作用。鉴于肝缺血再灌注（IR）损伤具有重要的临床意义，本研究探讨了VASP在肝缺血再灌注阶段的作用。
本研究报道，与野生型（wildtype, WT）对照小鼠相比，VASP基因缺陷（VASP−/−）小鼠的肝IR损伤程度显著减轻。该结果与血清乳酸脱氢酶（lactate dehydrogenase, LDH）、天冬氨酸转氨酶（aspartate aminotransferase, AST）及丙氨酸转氨酶（alanine aminotransferase, ALT）水平，以及缺血肝组织内血小板中性粒细胞复合物的存在状态相关，且通过小干扰RNA（siRNA）抑制VASP表达可验证该结论。
在采用骨髓嵌合小鼠开展的研究中，本研究证实造血源性VASP对肝损伤程度具有关键影响。通过前列腺素E1使VASP在Ser153位点发生磷酸化，或通过心房钠尿肽使VASP在Ser235位点发生磷酸化，均可显著减轻肝IR损伤，该效应与缺血肝组织内血小板中性粒细胞复合物的减少密切相关。
综上，本研究证实VASP及其磷酸化可作为未来肝保护策略的关键靶点。