Trichostatin A epigenetically increases calpastatinexpression and inhibits calpain activity andcalcium-induced SH-SY5Y neuronal cell toxicity

摘要

Calpains are involved in calcium-induced neuronal cell toxicity, which isassociated with the pathophysiology of Alzheimer’s disease (AD). Theactivity of calpains is regulated by the inhibitor calpastatin, and increasedactivity of calpains and decreased calpastastin are often found in AD. Histonedeacetylase (HDAC) inhibitors are implicated in AD treatmentthrough the improvement of learning and memory but the underlyingmechanism is yet to be understood. Here, using SH-SY5Y neuroblastomacells and a calcium ionophore ionomycin, we examined whether and howHDAC inhibitor trichostatin A (TSA) inhibits calcium-induced neuronalcell death. TSA increased both the mRNA and protein levels of calpastatin,with no alterations in those of calpain 1 and calpain 2. Furthermore,TSA-stimulated increase of calpastatin was accompanied by a significantattenuation of ionomycin-induced autolysis of calpain 1, but not of calpain2, and calpain-dependent 150 kDa aII spectrin cleavage. Under these conditions,however, caspase activity was unaltered. Moreover, ectopic expressionof small interfering RNA of calpastatin reversed the inhibitory effectof TSA on ionomycin-induced calpain 1 autolysis and aII spectrin cleavage.Chromatin immunoprecipitation assay revealed the increased levels ofacetylation at lysine 5 of histone H4 (H4K5-Ac), H3K9-Ac and H3K14-Acwithin the calpastatin promoter region in TSA-treated cells relative to controlcells. Finally, TSA significantly decreased ionomycin-induced cell toxicity.This study demonstrates that TSA attenuates calcium-induced neuronalcell death by the inhibition of calpain activity which is mediated in part byincreased calpastatin expression via histone hyperacetylation within the calpastatinpromoter region. Our study provides a novel mechanism for theneuroprotective effect of HDAC inhibitors on AD.