A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis
A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis
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DOI：
10.1016/j.bbrc.2017.05.109
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发表时间：
2017-07-15
影响因子：
3.1
通讯作者：
Sugawara, Akira
中科院分区：
文献类型：
--
作者：
Ito, Ryo;Sato, Ikuko;Sugawara, Akira
CYP 11B 2是参与盐皮质激素醛固酮合成的关键酶。CYP 11B 2在肾上腺中的表达受肾素-血管紧张素系统（RAS）控制，并且在维持高等生物体的电解质代谢中起重要作用。CYP 11B 2的异常过度表达导致矿物质平衡的破坏，并可导致高血压。虽然调控CYP 11B 2表达的分子机制仍然难以捉摸，我们假设，阻止CYP 11B 2表达的化合物可能代表一类新的抗高血压药物。在本研究中，我们建立了一个高通量筛选系统来鉴定此类化合物，并随后进行了化学筛选。我们发现，泛素-蛋白酶体抑制剂硼替佐米可抑制血管紧张素II（Ang II）诱导的肾上腺皮质H295 R细胞CYP 11 B2表达和醛固酮分泌。此外，硼替佐米下调Cyp 11b 2 mRNA的表达促进在筑波高血压小鼠的肾上腺，导致随后降低他们的血压。此外，我们观察到的特征性改变H3 K27 ac在肾上腺CYP 11B 2基因启动子诱导的血管紧张素II刺激，这被发现被破坏硼替佐米。总而言之，这些结果表明开发阻止CYP 11B 2表达的新型降压药物的可能性。(C)2017爱思唯尔公司All rights reserved.
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 over expression 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. (C) 2017 Elsevier Inc. All rights reserved.