Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA116921 | ENA |
REPOSITORIES: ENA
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Project description: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.
2009-05-02 | GSE15918 | GEO
Project description:Background: Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions — the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating pathologic increase in aldosterone synthase (CYP11B2) expression and aldosterone production. Elucidating the exact mechanisms causing aldosterone excess in primary aldosteronism would further the development of targeted treatments and alleviate the global hypertension burden.Methods: Next-generation sequencing analysis of formalin-fixed paraffin-embedded aldosterone-producing adenomas identified novel somatic variants in MCOLN3 (encoding the cation-permeable channel, TRPML3). Electrophysiologic, fura-2 calcium measurements, gene expression and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel MCOLN3 mutations. Results: Three somatic MCOLN3 variants (p.Y391D, p.F415I and p.N411_V412delinsI) were identified in four aldosterone-producing adenomas from male primary aldosteronism patients. Mutated MCOLN3 expressed in HAC15 cells resulted in a gain-of-function phenotype, which induced cell membrane depolarization and calcium influx and, in turn, triggered a significant increase in aldosterone synthase expression and aldosterone production. Conclusions: This is the first report of disease-causing MCOLN3 mutations in humans and first to implicate mutated MCOLN3 as a driver of dysregulated aldosterone production in primary aldosteronism.
2026-06-13 | GSE299739 | GEO
Project description:Background: Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. While gene mutations in APA trigger aldosterone overproduction via Calcium signaling, their precise regulatory mechanisms remain unclear. Our prior proteomic analysis identified significant upregulation of Tumor protein D52 (TPD52), an oncogene protein implicated in cancer progression, in APA. This study investigates the role of TPD52 in regulating aldosterone synthesis and its molecular mechanism. Method: TPD52 expression was validated in APA specimens. Gain- and loss-of-function studies in NCI-H295R cells were performed to assess its role in aldosterone synthesis. Mechanistic insights were obtained through transcriptomics and immunoprecipitation-mass spectrometry (IP-MS), with key results validated in NCI-H295R and HEK-293T cells. Results: TPD52 was upregulated in APA tissues. Functionally, TPD52 overexpression suppressed aldosterone synthesis in NCI-H295R cells, whereas its knockdown enhanced aldosterone production. Transcriptomics confirmed that TPD52 knockdown promoted CYP11B2 expression and aldosterone synthesis. IP-MS identified calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) as a novel TPD52-interacting protein. This interaction suppressed phosphorylation of calmodulin-dependent protein kinase 4 (CAMK4) and CREB. Importantly, CAMKK2 overexpression rescued the TPD52-mediated suppression of CYP11B2 expression and aldosterone synthesis. Conclusion: TPD52 acts as a negative regulator of aldosterone synthesis by inhibiting the CAMKK2–CAMK4–CREB signaling axis.
2026-02-22 | GSE319287 | GEO
Project description:Genome wide analysis of expression data in PBMC of three healthy male probands upon stimulation with vehicle only, aldosterone, cortisol, aldosterone and cortisol in physiological amounts in order to identify putative MR-target genes.
2024-09-13 | GSE162695 | GEO
Project description: Not available
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description: Not available
| S-EPMC5738339 | biostudies-literature
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description: Not available
| S-EPMC5935238 | biostudies-literature
Project description:Mechanism of lacritin-dependent production of the important dry eye mucin 'MUC16'
| PRJNA145025 | ENA