17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats

Abstract

Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.

The small heat shock protein HSPB1 protects mice from sepsis

“…Furthermore, HSP70 induction is impaired in ex-vivo lymphocytes of septic patients 31 , and HSP70 is a key determinant of mortality in aged septic hosts 26 . Increased HSP90 is also associated with an acute inflammatory-metabolic stress response in children with sepsis and multiple organ failure 32 , while inhibiting HSP90 ameliorates multiple organ dysfunction syndrome in rats subjected to endotoxemia 33 .…”

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

“…Previously, anti-inflammatory effects of HSP90 inhibition have been attributed to an induction of HSP70. 28 However, here the effects of EC144 on the inflammasome cannot be attributed to increased levels of HSP70, as its levels did not change with EC144 treatment ( Figure 1G).…”

Integration Analysis of m6A-SNPs and eQTLs Associated With Sepsis Reveals Platelet Degranulation and Staphylococcus aureus Infection are Mediated by m6A mRNA Methylation

“…Research on different phases of sepsis found that HSPA1B can be considered a serum marker for the acute proinflammatory phase (Gasparotto et al, 2018). Study on Multiple organ dysfunction syndrome in sepsis found that increased HSPA1B has an anti-inflammatory effect (Wang et al, 2016). In rats, raloxifene prevents severe sepsis through induction of HSPA1B with an anti-inflammatory effect (Shen et al, 2017).…”