Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Comparative Effects of Statins on Murine Cardiac Gene Expression Profiles in Normal Mice

ABSTRACT: Recent clinical data suggest that the efficacy of statin treatment in patients with heart failure varies depending on the drugs administered. Therefore, the present study was undertaken to compare murine cardiac gene expression following treatment with four different statins. Statins directly regulated cardiac gene expression in a drug-specific manner in mice. The influence of each statin on the cardiac mRNA expression of various genes, including several genes that might be involved in the development of cardiac disease, was not a general effect of this class of drugs. Male C57BL/6J mice (n = 20) were treated with or without a statin (pitavastatin calcium, pravastatin sodium, rosuvastatin calcium, or atorvastatin calcium hydrate) (n = 4 in each group) for four weeks. Total RNA was isolated from the left ventricle of each animal. The fragmented and labeled amplified cDNA was hybridized to a GeneChip Mouse Genome 430 2.0 Array (Affymetrix). Data and statistical analysis were performed with GeneSpring GX version 11.0 software (Agilent Technologies).

ORGANISM(S): Mus musculus

SUBMITTER: Masafumi Kumazaki

PROVIDER: E-GEOD-23101 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Comparative effects of statins on murine cardiac gene expression profiles in normal mice.

Kumazaki Masafumi M Ando Hitoshi H Ushijima Kentarou K Fujimura Akio A

European journal of pharmacology 20130321 1-3

Recent clinical data suggest that the efficacy of statin treatment in patients with heart failure varies depending on the drugs administered. The present study was undertaken to compare murine cardiac gene expression profiles following treatment with four different statins. In normal male C57BL/6J mice, 4 weeks of treatment with or without a statin (pitavastatin, pravastatin, rosuvastatin, or atorvastatin) did not affect any biochemical parameters, including the lipid profile. However, cardiac g ...[more]

PMID: 23524094

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Project description:Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of patients taking statins experience muscle related adverse events. Myalgia, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels, is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin-associated myalgia are not clearly understood. To elucidate changes in gene expression associated with statin-induced myalgia, we compared profiles of gene expression in the biopsied skeletal muscle from statin-intolerant patients undergoing statin re-challenge versus those of statin-tolerant controls. A robust separation of statin-intolerant and statin-tolerant cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of statin intolerant patients, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals are genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myopathy were observed with increased frequency among statin-intolerant study subjects.

Dataset Information

Comparative Effects of Statins on Murine Cardiac Gene Expression Profiles in Normal Mice

Publications

Comparative effects of statins on murine cardiac gene expression profiles in normal mice.

Similar Datasets

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