Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
J Steroid Biochem Mol Biol. 2019 Jan;185:137-141. doi: 10.1016/j.jsbmb.2018.08.007. Epub 2018 Aug 17.
Angiotensin 1-7 (Ang 1-7), which is a protein cleaved from angiotensin II (A-II), binds to the MAS receptor. Ang 1-7 has been demonstrated to exert protective effects against A-II-mediated cardiac, atherosclerotic, and renal damages. The aims of our study were to demonstrate the inhibitory role of Ang 1-7 in A-II-mediated aldosterone production by interacting with the MAS receptor in human adrenocortical carcinoma (HAC15) cells, and clarify the intracellular signaling mechanisms underlying the inhibition of aldosterone production by Ang 1-7. Ang 1-7 significantly suppressed A-II-stimulated aldosterone production, and partially abrogated A-II-induced upregulation of CYP11B2 expression. Treatment with a selective Ang 1-7 antagonist abrogated Ang 1-7-mediated inhibition of aldosterone production in HAC15 cells. Incubation of A-II-treated HAC15 cells with conditioned medium containing Ang 1-7 was demonstrated to suppress A-II-mediated aldosterone production and CYP11B2 expression. Proteomic analysis showed that Ang 1-7 predominantly inhibited the phosphorylation of JAK-STAT proteins in A-II stimulated HAC15 cells. Treatment of HAC15 cells with a STAT3 inhibitor partially but significantly repressed A-II-mediated aldosterone production by 63.2%. Similarly, treatment with a STAT5 inhibitor significantly abrogated A-II-stimulated aldosterone production in HAC15 cells by 60.7%. In conclusion, we demonstrated that Ang 1-7 negatively regulates A-II-mediated aldosterone production, and the observed inhibition of aldosterone production was associated with JAK/STAT signaling in human adrenal cells. Therefore, activation of Ang 1-7 or stimulation of the MAS receptor, which inhibits aldosterone production, is a promising therapeutic approach for the prevention of cardiovascular events that can directly affect the target organs.
血管紧张素 1-7（Ang 1-7）是血管紧张素 II（A-II）切割产生的一种蛋白，它与 MAS 受体结合。Ang 1-7 已被证明可发挥保护作用，防止 A-II 介导的心脏、动脉粥样硬化和肾脏损伤。我们的研究目的是证明 Ang 1-7 通过与人类肾上腺皮质癌细胞（HAC15）中的 MAS 受体相互作用，抑制 A-II 介导的醛固酮产生的抑制作用，并阐明 Ang 1-7 抑制醛固酮产生的细胞内信号机制。Ang 1-7 显著抑制 A-II 刺激的醛固酮产生，并部分阻断 A-II 诱导的 CYP11B2 表达上调。用选择性 Ang 1-7 拮抗剂处理可阻断 Ang 1-7 介导的 HAC15 细胞中醛固酮的产生。用含有 Ang 1-7 的条件培养基孵育 A-II 处理的 HAC15 细胞，可抑制 A-II 介导的醛固酮产生和 CYP11B2 表达。蛋白质组学分析表明，Ang 1-7 主要抑制 A-II 刺激的 HAC15 细胞中 JAK-STAT 蛋白的磷酸化。用 STAT3 抑制剂处理 HAC15 细胞，部分但显著地抑制了 A-II 介导的醛固酮产生，抑制率为 63.2%。同样，用 STAT5 抑制剂处理可显著抑制 A-II 刺激的 HAC15 细胞中醛固酮的产生，抑制率为 60.7%。总之，我们证明 Ang 1-7 负调节 A-II 介导的醛固酮产生，观察到的醛固酮产生抑制与人类肾上腺细胞中的 JAK/STAT 信号有关。因此，激活 Ang 1-7 或刺激 MAS 受体（抑制醛固酮产生）可能是预防心血管事件的一种有前途的治疗方法，因为心血管事件可以直接影响靶器官。
