Association of miR-145 with statin-induced skeletal muscle toxicity in human rhabdomyosarcoma RD cells.
J Pharm Sci. 2017 Apr 21;:
Authors: Saito S, Nakanishi T, Shirasaki Y, Nakajima M, Tamai I
Skeletal muscle toxicity including rhabdomyolysis in severe case is a major side effect of LDL cholesterol-lowering statin drugs. We, therefore, aimed to explore microRNA (miRNA) expression to understand molecular mechanism of statin-induced toxicity. miRNA expression profiling assay for cerivastatin (1 μM for 48 hr)-treated RD cells showed more than two-fold decrease in 26 miRNA expressions with miR-145 being down-regulated prominently. When RD cells were treated with cerivastatin at 10 μM for 36 hr, mitochondrial dysfunction was observed in 49.6% of the population without causing apoptosis, whereas 82% underwent apoptosis when treated at 10 μM for 48 hr. In RD cells treated under the same condition (10 μM for 48 hr), miR-145 expression and mRNA expressions of pro-apoptotic APAF1 and CASP10 genes, potential targets of miR-145, significantly decreased and increased, respectively. Moreover, enforced expression of miR-145 reduced apoptotic cell population of cerivastatin-treated RD cells (10 μM for 36 hr). Since miR-145 increased in extracellular medium from cerivastatin-treated RD cells, miR-145 was suggested to be secreted in response to statin-induced toxicity. These results provide a new rationale for statin's toxicity that statin-induced apoptosis is caused by enhanced expression of pro-apoptotic genes mediated by decreased intracellular miR-145 due to statin-induced mitochondrial dysfunction.
PMID: 28438533 [PubMed - as supplied by publisher]