Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
PLoS One. 2012;7(9):e44712. doi: 10.1371/journal.pone.0044712. Epub 2012 Sep 19.
Phosphoinositide-3-kinase (PI3K)/Akt dependent signaling has been shown to improve outcome in sepsis/septic shock. There is also ample evidence that PI3K/Akt dependent signaling plays a crucial role in maintaining normal cardiac function. We hypothesized that PI3K/Akt signaling may ameliorate septic shock by attenuating sepsis-induced cardiac dysfunction. Cardiac function and survival were evaluated in transgenic mice with cardiac myocyte specific expression of constitutively active PI3K isoform, p110α (caPI3K Tg). caPI3K Tg and wild type (WT) mice were subjected to cecal ligation/puncture (CLP) induced sepsis. Wild type CLP mice showed dramatic cardiac dysfunction at 6 hrs. Septic cardiomyopathy was significantly attenuated in caPI3K CLP mice. The time to 100% mortality was 46 hrs in WT CLP mice. In contrast, 80% of the caPI3K mice survived at 46 hrs after CLP (p<0.01) and 50% survived >30 days (p<0.01). Cardiac caPI3K expression prevented expression of an inflammatory phenotype in CLP sepsis. Organ neutrophil infiltration and lung apoptosis were also effectively inhibited by cardiac PI3k p110α expression. Cardiac high mobility group box-1 (HMGB-1) translocation was also inhibited by caPI3K p110α expression. We conclude that cardiac specific activation of PI3k/Akt dependent signaling can significantly modify the morbidity and mortality associated with sepsis. Our data also indicate that myocardial function/dysfunction plays a prominent role in the pathogenesis of sepsis and that maintenance of cardiac function during sepsis is essential. Finally, these data suggest that modulation of the PI3K/p110α signaling pathway may be beneficial in the prevention and/or management of septic cardiomyopathy and septic shock.
磷酸肌醇 3-激酶（PI3K）/Akt 依赖性信号已被证明可改善脓毒症/脓毒性休克的预后。也有充分的证据表明，PI3K/Akt 依赖性信号在维持正常心脏功能中起着至关重要的作用。我们假设 PI3K/Akt 信号可能通过减轻脓毒症引起的心脏功能障碍来改善脓毒性休克。在心肌细胞特异性表达组成型激活的 PI3K 同工型 p110α（caPI3K Tg）的转基因小鼠中评估心脏功能和存活率。caPI3K Tg 和野生型（WT）小鼠接受盲肠结扎/穿刺（CLP）诱导的脓毒症。WT CLP 小鼠在 6 小时时表现出明显的心脏功能障碍。在 caPI3K CLP 小鼠中，脓毒症性心肌病显著减轻。WT CLP 小鼠在 46 小时达到 100%死亡率，而 80%的 caPI3K 小鼠在 CLP 后 46 小时存活（p<0.01），50%存活超过 30 天（p<0.01）。心脏 caPI3K 表达可防止 CLP 脓毒症中炎症表型的表达。心脏 PI3K p110α 的表达还可有效抑制器官中性粒细胞浸润和肺细胞凋亡。心脏高迁移率族蛋白 B1（HMGB-1）易位也被 caPI3K p110α 的表达抑制。我们得出结论，心脏特异性激活 PI3K/Akt 依赖性信号可以显著改变与脓毒症相关的发病率和死亡率。我们的数据还表明，心肌功能/障碍在脓毒症发病机制中起着突出作用，在脓毒症期间维持心脏功能至关重要。最后，这些数据表明，PI3K/p110α 信号通路的调节可能有益于预防和/或管理脓毒性心肌病和脓毒性休克。
