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.
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Acknowledgements
The authors wish to acknowledge Celeste MK Tai for assistance with figures, Esther Boey for assistance with cell culture. This work was supported by the Victorian Government’s Operational Infrastructure Support Program. JRM is supported by a National Health and Medical Research Council Senior Research Fellowship (grant number 1078985). SBS is supported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarship.
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Bass-Stringer, S., Ooi, J.Y.Y. & McMullen, J.R. Clusterin is regulated by IGF1–PI3K signaling in the heart: implications for biomarker and drug target discovery, and cardiotoxicity. Arch Toxicol 94, 1763–1768 (2020). https://doi.org/10.1007/s00204-020-02709-2
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DOI: https://doi.org/10.1007/s00204-020-02709-2