ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapibs effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.
Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
Specimen part, Cell line, Time
View SamplesThree-day-old wild-type Col-0 plants grown on filter paper in the dark, as described above, were exposed to blue light and harvested after 1 hour exposure. Total RNAs were extracted using Trizol reagent (Life Technologies) and purified by PureLink RNA Mini Kits (Life Technologies). Directional RNA-seq libraries were constructed using TruSeq Small RNA Sample Prep Kits and TruSeq RNA Sample Preparation Kits according to the Directional mRNA-Seq Library Prep. Manual (Illumina) and sequenced using a HiSeq sequencer (Illumina).
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Age, Specimen part, Treatment
View SamplesIn order to identify genes downstream of MYB30 whose expression is regulated in the presence of H2O2.
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View SamplesTotal RNAs were extracted from internodes and roots of 18 day-after-germination soybean plants, and the expression levels of the genes that encode xylem sap associated peptides or proteins were analyzed.
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Specimen part
View SamplesA cohesin component RAD21 is recurrently mutated in myeloid neoplasms. To investigate the role of RAD21 mutation in leukemogenesis, we performed RNA sequencing of mock, wild-type or mutant RAD21 transduced Kasumi-1 cells and compared their effect on global gene expression.
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