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Series GSE15918 Query DataSets for GSE15918
Status Public on May 02, 2009
Title Torcetrapib induces aldosterone and cortisol production in an intracellular calcium-dependent mechanism
Organism Homo sapiens
Experiment type Expression profiling by array
Summary 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 torcetrapib’s 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.
 
Overall design Experimental Goals: 1. To determine whether or not CETP inhibitors induce activation of RAAS pathway in adrenal derived cells, 2. To determine whether adrenocortical cells show a transcriptional response that can be correlated to BP effects.
Experimental Background: Aldosterone production by H295R adrenocortical carcinoma cells in response to the treatments described [dimethyl sulfoxide (vehicle), angiotensin II (a CETP inhibitor), or test compound CP-529414 (a CETP inhibitor)] will be analyzed.
 
Contributor(s) Loging WT
Citation(s) 19164467
Submission date Apr 30, 2009
Last update date Mar 25, 2019
Contact name William Loging
E-mail(s) logingwt@msn.com
Organization name CETP Project Team
Street address 73 Skyline Dr
City Salem
State/province CT
ZIP/Postal code 06470
Country USA
 
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (9)
GSM399572 H295R_Group_A_Dose_NA_TIMEPT1_001
GSM399573 H295R_Group_A_Dose_NA_TIMEPT1_002
GSM399574 H295R_Group_A_Dose_NA_TIMEPT1_003
Relations
BioProject PRJNA116921

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE15918_RAW.tar 43.9 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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