Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Cardiovasc Res. 2011 Jan 1;89(1):109-18. doi: 10.1093/cvr/cvq268. Epub 2010 Aug 23.
cardiac dysfunction is a critical manifestation of severe sepsis/septic shock and is responsible for high mortality due to sepsis. Recent evidence suggests that angiogenic factors have a protective effect on sepsis-induced organ damage. Heat shock protein A12B (HSPA12B) is a newly discovered gene that is essential for angiogenesis. We hypothesized that overexpression of HSPA12B would induce protection against endotoxin-induced cardiac dysfunction.
to evaluate this hypothesis, we generated transgenic mice overexpressing the human hspa12b gene (Tg). Wild-type (WT) littermates served as controls. Tg and WT mice were treated with lipopolysaccharide (LPS) and cardiac function was measured after 6 h. LPS treatment caused cardiac dysfunction in WT mice. In contrast, cardiac function was significantly preserved in Tg mice following LPS administration. LPS increased the expression of vascular cell adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1) and leucocyte infiltration into the myocardium of WT mice. In Tg mice, LPS-increased VCAM-1/ICAM-1 expression and leucocyte infiltration were significantly attenuated. Overexpression of HSPA12B also prevented the decrement in the activation of phosphatidlyinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling in the myocardium. Importantly, PI3K inhibition with Wortmannin abolished the protection of HSPA12B against LPS-induced cardiac dysfunction.
these results suggest that HSPA12B plays an important role in the attenuation of endotoxin-induced cardiac dysfunction and that the mechanisms involve the preserved activation of PI3K/Akt signalling, resulting in attenuation of LPS-increased expression of VCAM-1/ICAM-1 and leucocyte infiltration into the myocardium.
心功能障碍是严重脓毒症/脓毒性休克的一种严重表现，也是导致脓毒症高死亡率的主要原因。最近的证据表明，血管生成因子对脓毒症引起的器官损伤具有保护作用。热休克蛋白 A12B（HSPA12B）是一种新发现的基因，对血管生成至关重要。我们假设 HSPA12B 的过表达将诱导对抗内毒素诱导的心功能障碍的保护作用。
为了验证这一假设，我们生成了过表达人 hspa12b 基因的转基因小鼠（Tg）。野生型（WT）同窝仔作为对照。Tg 和 WT 小鼠用脂多糖（LPS）处理，并在 6 小时后测量心脏功能。LPS 处理导致 WT 小鼠心脏功能障碍。相比之下，LPS 处理后 Tg 小鼠的心脏功能明显得到保护。LPS 增加了血管细胞黏附分子-1（VCAM-1）/细胞间黏附分子-1（ICAM-1）的表达和白细胞浸润到 WT 小鼠的心肌。在 Tg 小鼠中，LPS 增加的 VCAM-1/ICAM-1 表达和白细胞浸润明显减弱。HSPA12B 的过表达也防止了心肌中磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）信号的激活降低。重要的是，用 Wortmannin 抑制 PI3K 消除了 HSPA12B 对 LPS 诱导的心功能障碍的保护作用。
这些结果表明 HSPA12B 在减轻内毒素诱导的心功能障碍中起着重要作用，其机制涉及 PI3K/Akt 信号的保存激活，导致 LPS 增加的 VCAM-1/ICAM-1 表达和白细胞浸润到心肌的减少。
