Attenuation Of Cardiac Dysfunction By HSPA12B In Mouse Endotoxin-induced Sepsis

BackgroundCardiac dysfunction is a critical manifestation of severe sepsis shock and is responsible for high mortality of sepsis. Recent evidence suggests that angiogenic factors play a critical role in the development of sepsis-induced injury. HSPA12B is a newly discovered gene that has been shown essential for angiogenesis. So we hypothesized that overexpression of HSPA12B would induce protection against endotoxin-induced cardiac dysfunction.TLR4/NF-κB signaling pathway is excessively actived and which casused excessively inflammatory reaction. It is the critical factor that causes sepsis-induced heart failure. Sepsis-induced vascular inflammation and endothelial dysfunction are associated with a loss of eNOS and overproduction of iNOS, which causes vasodilation and acts as one of the key mediators of inflammationHeat shock protein A12B (HSPA12B) was discovered by Han et al in 2003 . Subsequently, HSPA12B was identified as the newest member of HSP70 family proteins and mainly expressed in endothelial cells . Recently, HSPA12B has been demonstrated to play an essential role in the induction of angiogenesis in vitro, partially attributable to activation of Akt . Akt is a critical kinase in PI3K/Akt signaling pathway, which has been shown to play important roles in limiting proinflammatory response during sepsis/septic shock both in vitro and in vivo.SubjectThis study will test the hypothesis that overexpression of HSPA12B would protect against endotoxin-induced cardiac dysfunction.Methods Transgenic female mice overexpressing human hspa12b gene (Tg) and wild type littermates (WT) at 2-month of age were injected with (lipopolysaccharide, LPS). Cardiac dysfunction was evaluated by echocardiography and the activation of PI3K/Akt signaling pathway was determined by western blot.ResultLPS treatment significantly decreased ejection fraction and fraction shortening in WT mice. In contrast, LPS-induced cardiac dysfunction was significantly attenuated in Tg mice. LPS administration significantly increased the expression of VCAM-1/ICAM-1 and leukocyte infiltration in the myocardium of WT mice. However, the increased VCAM-1/ICAM-1 expression and leukocyte infiltration by LPS was significantly reduced in Tg mice. Overexpression of HSPA12B also significantly prevented the decrease of eNOS and the increase of iNOS in the myocardium following LPS treatment. Moreover, overexpression of HSPA12B significantly attenuated LPS-reduced the levels of phospho-Akt and phospho-GSK-3βand prevented LPS-decreased angiopoietin-1 expression in the myocardium. Importantly, PI3K inhibition with Wortmannin abolished the protection of HSPA12B against LPS-induced cardiac dysfunction.ConclusionThese results suggest that HSPA12B plays an important role in attenuation of endotoxin-induced cardiac dysfunction and that the mechanisms may involve the preserved activation of PI3K/Akt signaling pathway...