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J Pharm Sci. 2017 Sep;106(9):2873-2880. doi: 10.1016/j.xphs.2017.04.005. Epub 2017 Apr 21.

Association of miR-145 With Statin-Induced Skeletal Muscle Toxicity in Human Rhabdomyosarcoma RD Cells.

Author information

1
Department of Membrane Transport and Biopharmaceutics, and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
2
Department of Membrane Transport and Biopharmaceutics, and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.

Abstract

Skeletal muscle toxicity including rhabdomyolysis in severe case is a major side effect of low-density lipoprotein cholesterol-lowering statin drugs. We, therefore, aimed at exploring microRNA (miRNA) expression to understand molecular mechanism of statin-induced toxicity. miRNA expression profiling assay for cerivastatin (1 μM for 48 h)-treated RD cells showed more than 2-fold decrease in 26 miRNA expressions with miR-145 being downregulated prominently. When RD cells were treated with cerivastatin at 10 μM for 36 h, mitochondrial dysfunction was observed in 49.6% of the population without causing apoptosis, whereas 82% underwent apoptosis when treated at 10 μM for 48 h. In RD cells treated under the same condition (10 μM for 48 h), miR-145 expression and mRNA expressions of proapoptotic 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 h). Because 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 proapoptotic genes mediated by decreased intracellular miR-145 due to statin-induced mitochondrial dysfunction.

KEYWORDS:

apoptosis; biomarker; miR-145; microRNA; skeletal muscle toxicity; statins

PMID:
28438533
DOI:
10.1016/j.xphs.2017.04.005
[Indexed for MEDLINE]

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