A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis

Ryo Ito, Ikuko Sato, Tadayuki Tsujita, Atsushi Yokoyama, Akira Sugawara

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)21-28
ページ数8
ジャーナルBiochemical and biophysical research communications
489
1
DOI
出版ステータスPublished - 2017 7 15

ASJC Scopus subject areas

  • 生物理学
  • 生化学
  • 分子生物学
  • 細胞生物学

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