Pipicz Márton, Kocsis Gabriella F, Sárváry-Arantes László, Bencsik Péter, Varga Zoltán V, Ferdinandy Péter, Csont Tamás
Department of Biochemistry, Faculty of Medicine, University of Szeged, Dóm tér. 9., H-6720 Szeged, Hungary.
Pharmahungary 2000 Ltd., Dóm tér. 9., H-6720 Szeged, Hungary.
Molecules. 2017 Mar 8;22(3):433. doi: 10.3390/molecules22030433.
Administration of low-dose endotoxin (lipopolysaccharide, LPS) 24 h before a lethal ischemia induces pharmacological late preconditioning. The exact mechanism of this phenomenon is not clear. Here we aimed to investigate whether low-dose LPS exerts late effects on peroxynitrite formation and activation of Akt, Erk, and STAT3 in the heart. Male Wistar rats were injected with LPS (S. typhimurium; 0.5 mg/kg i.p.) or saline. Twenty-four hours later, hearts were isolated, perfused for 10 min, and then used for biochemical analyses. LPS pretreatment enhanced cardiac formation of the peroxynitrite marker 3-nitrotyrosine. LPS pretreatment also increased cardiac levels of the peroxynitrite precursor nitric oxide (NO) and superoxide. The activities of Ca2+-independent NO synthase and xanthine oxidoreductase increased in LPS-pretreated hearts. LPS pretreatment resulted in significantly enhanced phosphorylation of STAT3 and non-significantly increased phosphorylation of Akt without affecting the activation of Erk. In separate experiments, isolated working hearts were subjected to 30 min global ischemia and 20 min reperfusion. LPS pretreatment significantly improved ischemia-reperfusion-induced deterioration of cardiac function. We conclude that LPS pretreatment enhances cardiac peroxynitrite formation and activates STAT3 24 h later, which may contribute to LPS-induced late preconditioning.
在致死性缺血前24小时给予低剂量内毒素（脂多糖，LPS）可诱导药理学晚期预处理。这种现象的确切机制尚不清楚。在此，我们旨在研究低剂量LPS是否对心脏中过氧亚硝酸盐的形成以及Akt、Erk和STAT3的激活产生晚期影响。雄性Wistar大鼠注射LPS（鼠伤寒沙门氏菌；0.5mg/kg腹腔注射）或生理盐水。24小时后，分离心脏，灌注10分钟，然后用于生化分析。LPS预处理增强了过氧亚硝酸盐标志物3-硝基酪氨酸的心脏形成。LPS预处理还增加了过氧亚硝酸盐前体一氧化氮（NO）和超氧化物的心脏水平。在LPS预处理的心脏中，不依赖Ca2+的NO合酶和黄嘌呤氧化还原酶的活性增加。LPS预处理导致STAT3的磷酸化显著增强，Akt的磷酸化非显著增加，而不影响Erk的激活。在单独的实验中，分离的工作心脏经历30分钟全心缺血和20分钟再灌注。LPS预处理显著改善了缺血-再灌注诱导的心脏功能恶化。我们得出结论，LPS预处理可增强心脏过氧亚硝酸盐的形成，并在24小时后激活STAT3，这可能有助于LPS诱导的晚期预处理。
