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Eicosapentaenoic acid attenuates statin-induced ER stress and toxicity in myoblast
Masahiko Ohta1, Hiroyuki Kawano, Tatsuto Notsu
1Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
Abstract:
We previously reported that eicosapentaenoic acid (EPA) improved statin-induced rhabdomyolysis in rats (Naba et al. [6]). In this study, we report for the first time direct improvement by EPA of statin-induced toxicity in cultured myoblasts and the mechanistic involvement of endoplasmic reticulum (ER) stress. Differentiated rhabdomyosarcoma cells (RD cells) were treated with statins and EPA for 1-4days. Statins induced various toxic changes in RD cells, and EPA attenuated all of these changes. Interestingly, statins increased mRNA expression of ER stress markers (XBP-1 and CHOP) and EPA attenuated both. Further, in a statin-induced rat model of rhabdomyolysis, these markers in skeletal muscle were significantly correlated with plasma CPK activity. In RD cells, statins also increased p-c-Jun protein content and caspase-3/7 activity, while 4-PBA, an ER stress attenuator, PPAR-δ agonist, and EPA attenuated them. These findings suggest that EPA attenuates statin-induced ER stress, JNK activation and toxicity in cultured myoblast cells, and that PPAR-δ may mechanically involved in the effects of EPA.
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