Abstract

Open-access gene expression data sets provide a useful resource for identifying novel drug targets and biomarkers. The IGF1–PI3K pathway is a critical mediator of physiological cardiac enlargement/hypertrophy and protection. This study arose after mining a gene microarray data set from a previous study that compared heart tissue from cardiac-specific PI3K transgenic mouse models. The top-ranked candidate identified from the microarray data was clusterin. Clusterin has been proposed as a biomarker for multiple diseases including heart failure, and as a cancer drug target. Here, we show that clusterin gene expression is increased in hearts of transgenic mice with increased PI3K and decreased in mice with depressed cardiac PI3K. In vitro, clusterin secretion was elevated in media from neonatal rat ventricular myocytes treated with IGF1. Furthermore, by mining gene expression data from hearts during normal mouse postnatal growth, we also report an increase in clusterin expression with postnatal heart growth. Given we show that clusterin is regulated by the IGF1–PI3K pathway in the heart, and this pathway mediates physiological cardiac hypertrophy and cardioprotection, caution is required when considering clusterin as a biomarker for heart failure and as a cancer target. Mining pre-existing cardiac profiling data sets may be a useful approach to assess whether regulating new drug targets is likely to lead to cardiac damage/toxicity.

中文翻译：

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簇蛋白由心脏中的IGF1-PI3K信号传导调节：对生物标志物和药物靶标发现以及心脏毒性的影响。

摘要

开放获取基因表达数据集为鉴定新型药物靶标和生物标志物提供了有用的资源。IGF1-PI3K途径是生理性心脏扩大/肥大和保护的关键介质。这项研究是在挖掘先前研究的基因芯片数据集之后进行的，该研究比较了心脏特异性PI3K转基因小鼠模型的心脏组织。从微阵列数据中识别出的排名最高的候选者是clusterin。簇蛋白已被提议作为包括心力衰竭在内的多种疾病的生物标志物，并被用作癌症药物靶标。在这里，我们显示簇蛋白基因表达在PI3K增加的转基因小鼠心脏中增加，而在心脏PI3K降低的小鼠中减少。在体外，用IGF1处理的新生大鼠心室肌细胞的培养基中簇蛋白分泌增加。此外，通过挖掘正常小鼠出生后心脏中心脏的基因表达数据，我们还报告了簇蛋白表达随出生后心脏生长而增加。鉴于我们表明簇蛋白受心脏中IGF1-PI3K通路的调节，并且该通路介导了生理性心肌肥大和心脏保护作用，因此在考虑将簇蛋白作为心力衰竭的生物标志物和癌症靶标时需要谨慎。挖掘预先存在的心脏概况数据集可能是一种有用的方法，用于评估调节新药物靶标是否可能导致心脏损害/毒性。并且该途径介导了生理性心脏肥大和心脏保护作用，因此在考虑将簇蛋白作为心力衰竭的生物标志物和癌症靶标时需要谨慎。挖掘预先存在的心脏概况数据集可能是一种有用的方法，用于评估对新药物靶标的调节是否可能导致心脏损害/毒性。并且该途径介导了生理性心脏肥大和心脏保护作用，因此在考虑将簇蛋白作为心力衰竭的生物标志物和癌症靶标时需要谨慎。挖掘预先存在的心脏概况数据集可能是一种有用的方法，用于评估对新药物靶标的调节是否可能导致心脏损害/毒性。