Attenuation of cardiac dysfunction by HSPA12B in endotoxin-induced sepsis in mice through a PI3K-dependent mechanism

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.