The extracellular sulfatases (exSulfs) sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2) are well-known regulators of cell signaling and metabolism. In addition, exSulfs mediate the up- or downregulatory effects of cytokines on angiotensin II (Ang II)-induced expression of hypertensive mediators in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHRs). Previously, we demonstrated that interleukin-10 (IL-10)-induced dimethylarginine dimethylaminohydrolase-1 (DDAH-1) expression was mediated by Ang II subtype 2 receptor (AT2 R) and AMP-activated protein kinase (AMPK) activation, and that IL-10-mediated inhibition of Ang II-induced proliferation of SHRs VSMC was partially associated with DDAH-1. In this study, we examined the effects of exSulfs on IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation of SHRs VSMC. IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation were attenuated in Sulf1 siRNA-transfected SHRs VSMC. However, Sulf2 did not affect IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation. Downregulation of Sulf1 inhibited IL-10-induced AT2 R expression and the synergistic effects of IL-10 on Ang II-induced AT2 R expression. Additionally, Sulf1 downregulation inhibited IL-10-induced AMPK activity and abrogation of Ang II-induced decrease in AMPK activity. Moreover, the IL-10-mediated inhibition of Ang II-induced proliferation was not detected in Sulf1 siRNA-transfected SHRs VSMC; IL-10-mediated inhibition of Ang II-induced VSMC proliferation was mediated via the AT2 R pathway and AMPK activation. Specifically, IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation, which is mediated by the AT2 R pathway and AMPK activation, are mainly mediated by Sulf1 activity in SHRs VSMC. These results suggest that Sulf1, and not Sulf2, mediates the IL-10-induced inhibition of Ang II-induced hypertensive effects in SHRs VSMC.

中文翻译：

---

硫酸酯酶1介导自发性高血压大鼠血管平滑肌细胞中IL-10诱导的二甲基精氨酸二甲氨基水解酶1的表达和抗增殖作用

细胞外硫酸酯酶 (exSulfs) 硫酸酯酶 1 (Sulf1) 和硫酸酯酶 2 (Sulf2) 是众所周知的细胞信号传导和代谢调节剂。此外，exSulfs 介导细胞因子对血管紧张素 II (Ang II) 诱导的自发性高血压大鼠 (SHR) 血管平滑肌细胞 (VSMC) 中高血压介质表达的上调或下调作用。以前，我们证明白介素-10 (IL-10) 诱导的二甲基精氨酸二甲氨基水解酶-1 (DDAH-1) 表达是由 Ang II 亚型 2 受体 (AT2 R) 和 AMP 活化蛋白激酶 (AMPK) 激活介导的，并且IL-10 介导的对 Ang II 诱导的 SHR VSMC 增殖的抑制与 DDAH-1 部分相关。在这项研究中，我们检查了 exSulfs 对 IL-10 诱导的 DDAH-1 表达的影响，取消了 Ang II 诱导的 DDAH-1 下调，和抑制 Ang II 诱导的 SHRs VSMC 增殖。IL-10 诱导的 DDAH-1 表达和 Ang II 诱导的 DDAH-1 下调的消除在 Sulf1 siRNA 转染的 SHR VSMC 中减弱。然而，Sulf2 不影响 IL-10 诱导的 DDAH-1 表达和消除 Ang II 诱导的 DDAH-1 下调。Sulf1 的下调抑制了 IL-10 诱导的 AT2 R 表达和 IL-10 对 Ang II 诱导的 AT2 R 表达的协同作用。此外，Sulf1 下调抑制了 IL-10 诱导的 AMPK 活性，并消除了 Ang II 诱导的 AMPK 活性降低。此外，在 Sulf1 siRNA 转染的 SHR VSMC 中未检测到 IL-10 介导的 Ang II 诱导的增殖抑制；IL-10 介导的 Ang II 诱导的 VSMC 增殖抑制是通过 AT2 R 通路和 AMPK 激活介导的。具体来说，IL-10 诱导的 DDAH-1 表达、Ang II 诱导的 DDAH-1 下调的消除和 Ang II 诱导的增殖的抑制（由 AT2 R 通路和 AMPK 激活介导）主要由 SHR 中的 Sulf1 活性介导VSMC。这些结果表明 Sulf1 而不是 Sulf2 介导了 IL-10 诱导的对 SHR VSMC 中 Ang II 诱导的高血压作用的抑制。