A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis
| Autor: | Atsushi Yokoyama, Ryo Ito, Ikuko Sato, Akira Sugawara, Tadayuki Tsujita |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Cell Survival medicine.drug_class Biophysics Down-Regulation Mice Transgenic Stimulation Pharmacology Biology Biochemistry Gene Expression Regulation Enzymologic Bortezomib Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Internal medicine medicine Animals Cytochrome P-450 CYP11B2 Humans Secretion Aldosterone Molecular Biology Cells Cultured chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Adrenal gland Angiotensin II Cell Biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Endocrinology Enzyme chemistry Mineralocorticoid Female medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 489:21-28 |
| ISSN: | 0006-291X |
| Popis: | CYP11B2 is a key enzyme involved in the synthesis of the mineralocorticoid aldosterone. CYP11B2 expression in the adrenal glands is controlled by the renin-angiotensin system (RAS), and plays an important role in the maintenance of electrolyte metabolism in higher organisms. Abnormal overexpression of CYP11B2 results in the disruption of mineral balance and can lead to hypertension. Though the molecular mechanism of the regulation of CYP11B2 expression has remained elusive, we hypothesize that compounds that prevent CYP11B2 expression could represent a novel class of antihypertensive drugs. In this study, we established a high-throughput screening system to identify such compounds, and subsequently carried out chemical screening. We found that the ubiquitin-proteasome inhibitor bortezomib could suppress CYP11B2 expression and secretion of aldosterone induced by angiotensin II (Ang II) in adrenocortical H295R cells. Moreover, bortezomib down-regulated the Cyp11b2 mRNA expression facilitated in the adrenal gland of Tsukuba hypertensive mice, resulting in subsequent lowering of their blood pressures. Furthermore, we observed the characteristic alteration of H3K27ac in the adrenal CYP11B2 gene promoter induced by Ang II stimulation, which was found to be disrupted by bortezomib. Taken together, these results suggest the possibility of developing novel antihypertensive drugs that prevent CYP11B2 expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect