Role of HSP90 in suppressing TLR4-mediated inflammation in ischemic postconditioning

Abstract

BACKGROUND: Myocardial inflammation mediated by toll-like receptor 4 (TLR4) plays an active role in myocardial ischemia/reperfusion (I/R) injury. Studies show that heat shock protein 90 (HSP90) is involved in ischemic postconditioning (IPostC) cardioprotection. This study investigates the roles of TLR4 and HSP90 in IPostC. METHODS: Rats were subjected to 30 min ischemia, then 2 h reperfusion. IPostC was applied by three cycles of 30 s reperfusion, then 30 s reocclusion at reperfusion onset. Sixty rats were randomly divided into four groups: sham, I/R, IPostC, and geldanamycin (GA, HSP90 inhibitor, 1 mg/kg) plus IPostC (IPostC + GA). RESULTS: IPostC significantly reduced I/R-induced infarct size (40.2±2.1% versus 28.4±2.4%; P < 0.05); the release of cardiac Troponin T, creatine kinase-MB, and lactate dehydrogenase (191.5±3.1 versus 140.6±3.3 pg/ml, 3394.6±132.7 versus 2880.7±125.5 pg/ml, 2686.2±98.6 versus 1848.8±90.1 pg/ml, respectively; P < 0.05); and cardiomyocyte apoptosis (40.3±2.2% versus 27.0±1.6%; P < 0.05). Further, local and circulating IL-1β, IL-6, TNF-α, and ICAM-1 levels decreased; TLR4 expression and nuclear factor-KB (NF-κB) signaling decreased; and cardiac HSP90 expression increased. Blocking HSP90 function with GA inhibited IPostC protection and anti-inflammation, suggesting that IPostC has a HSP90-dependent anti-inflammatory effect. CONCLUSION: HSP90 may play a role in IPostC-mediated cardioprotection by inhibiting TLR4 activation, local and systemic inflammation, and NF-kB signaling.