Oxidative injury to cardiomyocytes plays a critical role in cardiac pathogenesis following myocardial infarction. Transplantation of stem cell-derived cardiomyocytes has recently progressed as a novel treatment to repair damaged cardiac tissue but its efficacy has been limited by poor survival of transplanted cells owing to oxidative stress in the post-Transplantation environment. Identification of small molecules that activate cardioprotective pathways to prevent oxidative damage and increase survival of stem cells post-Transplantation is therefore of great interest for improving the efficacy of stem cell therapies. This report describes a chemical biology phenotypic screening approach to identify and validate small molecules that protect human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from oxidative stress. A luminescence-based high-Throughput assay for cell viability was used to screen a diverse collection of 48,640 small molecules for protection of hiPSC-CMs from peroxide-induced cell death. Cardioprotective activity of "hit" compounds was confirmed using impedance-based detection of cardiomyocyte monolayer integrity and contractile function. Structure-Activity relationship studies led to the identification of a potent class of compounds with 4-(pyridine-2-yl)thiazole scaffold. Examination of gene expression in hiPSC-CMs revealed that the hit compound, designated cardioprotectant 312 (CP-312), induces robust upregulation of heme oxygenase-1, amarker of the antioxidant response network that has been strongly correlated with protection of cardiomyocytes from oxidative stress. CP-312 therefore represents a novel chemical scaffold identified by phenotypic high-Throughput screening using hiPSC-CMs that activates the antioxidant defense response and may lead to improved pharmacological cardioprotective therapies.
CITATION STYLE
Kirby, R. J., Divlianska, D. B., Whig, K., Bryan, N., Morfa, C. J., Koo, A., … Malany, S. (2018). Discovery of novel small-molecule inducers of heme oxygenase-1 that protect human ipsc-derived cardiomyocytes from oxidative stress. Journal of Pharmacology and Experimental Therapeutics, 364(1), 87–96. https://doi.org/10.1124/jpet.117.243717
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