Cardiac-Specific Expression of Heat Shock Protein 27 Attenuated Endotoxin-Induced Cardiac Dysfunction and Mortality in Mice Through a Pi3k/Akt-Dependent Mechanism

Abstract

Cardiac dysfunction is a major consequence of septic shock and may be responsible for the high mortality of sepsis. We have reported that transgenic mice with cardiac-specific overexpression of heat shock protein 27 (Hsp27 Tg) exhibited the protection against doxorubicin-induced cardiac dysfunction. We hypothesized that overexpression of Hsp27 will attenuate cardiac dysfunction during endotoxemia. Hsp27 Tg and age-matched wild-type (WT) mice were injected with LPS. Cardiac function was evaluated by echocardiography, survival rate was carefully monitored, and activities of signaling pathways were determined by immunoblot. LPS administration significantly decreased cardiac function in WT mice. In Hsp27 Tg mice, LPS-induced cardiac dysfunction was significantly attenuated as evidenced by increased ejection fraction (27.3%) and fractional shortening (37.1%), respectively, compared with LPS-treated WT mice. Heat shock protein 27 Tg mice were more resistant to LPS-induced mortality than WT. The levels of phospho-Akt and phospho-glycogen synthase kinase 3beta (phospho-GSK-3beta) in the myocardium were significantly increased in Hsp27 Tg mice compared with WT after LPS administration. Nuclear factor kappaB-binding activity was significantly decreased in Hsp27 Tg mice compared with WT mice after LPS challenge. Similar results were observed in in vitro studies using Hsp27-transfected rat cardiomyoblasts. Importantly, phosphoinositide 3-kinase inhibition abolished the protective effect of Hsp27 in LPS-induced cardiac dysfunction and mortality of endotoxemia. Our results suggest that Hsp27 plays an important role in attenuation of cardiac dysfunction and mortality in endotoxemia and that the mechanisms of the protection may involve activation of the PI3K/Akt signaling pathway.

Involvement of Reductive Stress in the Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Heat Shock Protein 27

“…12,13 We have shown previously that moderate expression of Hsp27 in cardiomyocytes protects the myocardium against doxorubicin-induced cardiac dysfunction through antioxidative stress 11 and attenuates endotoxin-induced myocardium injury. 14 To test this possibility, we generated Tg mice with cardiacspecific expression of Hsp27 (Hsp27 Tg) at different expression levels. We found that reductive stress and cardiomyopathy were exhibited in the hearts of high levels of Hsp27 Tg mice while not in the moderate levels of Hsp27 Tg mice.…”

Effects of a GSK-3β inhibitor on the renal expression levels of RANK, RANKL and NF-κB in a rat model of diabetic nephropathy

“…Therefore, inhibition of GSK-3β may serve a crucial function in the regulation of inflammation (43). Since inflammation is a key factor underlying the pathogenesis of DN (44)(45)(46), GSK-3β inhibition may be considered a promising therapeutic target.…”

Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4

“…In this regard, overexpression of HSP27 protects cardiac myocytes against ischemic injury (44) and cardiac-specific expression of HSP27 protects against endotoxin-induced cardiac dysfunction (45). However, HSP27 exerts a protective effect when located in the cell.…”

“…Several endogenous factors including HSP60 (26,49), HSP70 (25,50), constitutive heat shock cognate protein HSC70 (24,31), coldinducible RNA-binding protein (51), HMGB1 (27,52) and cardiac myosin (28) have been reported to activate TLR4 in cell culture systems or in tissues. Whereas intracellular HSP27 activates the phosphatidylinositol 3-kinase/Akt pathway to exert a protective effect against myocardial injury (45), extracellular HSP27 appears to be an endogenous TLR4 activator in the myocardium and plays a role in the enhanced myocardial inflammatory response to I/R in aging hearts. The findings are consistent with our recent observation that extracellular HSP27 activates NF-κB and evokes an inflammatory response in cardiac microvascular ECs through a mechanism involving TLR4 (30).…”

“…However, HSP27 exerts a protective effect when located in the cell. Intracellular HSP27 is known to activate the phosphatidylinositol 3-kinase/Akt pathway (46), and this survival pathway plays an important role in mediating the cardioprotective effect of intracellular HSP27 (45). Recent data Figure 5.…”