A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.
A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.
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系统生物学策略揭示了生物学途径和血浆生物标志物候选物，以毒性他汀类药物诱导的肌肉变化。
DOI：
10.1371/journal.pone.0000097
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发表时间：
2006-12-20
期刊：
影响因子：
3.7
通讯作者：
Oresic, Matej
中科院分区：
文献类型：
--
作者：
Laaksonen, Reijo;Katajamaa, Mikko;Paiva, Hannu;Sysi-Aho, Marko;Saarinen, Lilli;Junni, Paivi;Lutjohann, Dieter;Smet, Joel;Van Coster, Rudy;Seppanen-Laakso, Tuulikki;Lehtimaki, Terho;Soini, Juhani;Oresic, Matej
高剂量他汀类药物积极降脂可增加他汀类药物诱导肌病的风险。然而，导致肌肉损伤的细胞机制尚不清楚，需要敏感的生物标志物来识别有发生他汀类药物诱导的严重副作用风险的患者。我们对肌肉标本的全基因组表达谱进行了生物信息学分析，并对早期随机试验中接受高剂量辛伐他汀（80 mg）、阿托伐他汀（40 mg）或安慰剂的患者的血浆样本进行了基于UPLC/MS的脂质组学分析。高剂量辛伐他汀治疗导致111个差异表达基因（1.5倍变化，p值<0.05），而安慰剂组和阿托伐他汀组分别只有1个和5个基因的表达发生改变。基因集富集分析鉴定了高剂量辛伐他汀后肌肉中几种受影响的途径（23个基因列表，错误发现率q值<0.1），包括类花生酸合成和磷脂酶C途径。使用脂质组学分析，我们确定了以前未表征的药物特异性变化的血浆脂质谱，尽管类似的他汀类药物诱导的血浆LDL-胆固醇的变化。我们还发现辛伐他汀治疗后血浆脂质组学变化与花生四烯酸5-脂氧合酶激活蛋白的肌肉表达相关。高剂量辛伐他汀影响骨骼肌中的多种代谢和信号通路，包括促炎通路。因此，我们的研究结果表明，临床上使用的高剂量他汀类药物可能会导致非肝组织中的意外代谢效应。脂质组学特征可以作为他汀类药物诱导的肌肉代谢改变的高度敏感的生物标志物，因此可以使我们能够识别应该用较低剂量治疗以防止可能的毒性的患者。
Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo. High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.
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影响因子：
5
作者：
Nelson, J;Jiang, XC;Shea, S
通讯作者：
Shea, S
影响因子：
2.4
作者：
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影响因子：
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作者：
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通讯作者：
Engelmann, B
DOI：
10.1016/0169-7439(93)85002-x
发表时间：
1993-03-01
影响因子：
3.9
作者：
DEJONG, S
通讯作者：
DEJONG, S
影响因子：
5.8
作者：
Katajamaa, M;Miettinen, J;Oresic, M
通讯作者：
Oresic, M