Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
PLoS One. 2011;6(12):e29494. doi: 10.1371/journal.pone.0029494. Epub 2011 Dec 22.
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 Ser(153) through Prostaglandin E1 or on Ser(235) 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.
最近的研究表明，血小板中性粒细胞复合物（PNC）的形成会影响炎症组织损伤。血管扩张刺激磷蛋白（VASP）在控制 PNC 的形成和心肌再灌注损伤中起着至关重要的作用。鉴于肝 IR 损伤的临床重要性，我们在肝缺血后继发再灌注期间研究了 VASP 的作用。我们在这里报告说，与野生型（WT）对照相比，VASP(-/-)动物的肝 IR 损伤减少。这与血清乳酸脱氢酶（LDH）、天冬氨酸（AST）和丙氨酸（ALT）转氨酶的水平以及缺血性肝组织中 PNC 的存在相关，并且可以通过使用 siRNA 抑制 VASP 来证实。在使用骨髓嵌合小鼠的研究中，我们发现造血 VASP 对肝损伤的程度至关重要。通过前列腺素 E1 使 VASP 丝氨酸（Ser）153 磷酸化，或通过心钠肽使 VASP 丝氨酸（Ser）235 磷酸化，可显著减轻肝 IR 损伤。这与缺血性肝组织中 PNC 的减少有关。总之，这些研究确定了 VASP 和 VASP 磷酸化是未来肝保护策略的关键靶点。
