title: Eicosapentaenoic acid attenuates statin-induced ER stress and toxicity in myoblast.
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.
authors: Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors: Masahiko
authors: M
authors: Ohta
authors: Hiroyuki
authors: H
authors: Kawano
authors: Tatsuto
authors: T
authors: Notsu
authors: Hiroyasu
authors: H
authors: Naba
authors: Kazunori
authors: K
authors: Imada
mesh_terms: D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D051381:Rats
chemical_list: C121358:4-phenylbutylamine; D002082:Butylamines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D015118:Eicosapentaenoic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053179:Caspase 7