Department of Microbiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Department of Microbiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Cytokine. 2021 Jan;137:155344. doi: 10.1016/j.cyto.2020.155344. Epub 2020 Oct 28.
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 (AT 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 AT R expression and the synergistic effects of IL-10 on Ang II-induced AT 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 AT 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 AT 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.
细胞外硫酸酯酶（exSulfs）中的硫酸酯酶 1（Sulf1）和硫酸酯酶 2（Sulf2）是细胞信号转导和代谢的已知调节剂。此外，exSulfs 介导细胞因子对血管平滑肌细胞（VSMC）中血管紧张素 II（Ang II）诱导的高血压介质表达的上调或下调作用，这种作用在自发性高血压大鼠（SHR）中尤为明显。之前，我们已经证明，白细胞介素-10（IL-10）诱导的二甲基精氨酸二甲氨基水解酶-1（DDAH-1）表达是由血管紧张素 II 亚型 2 受体（AT R）和 AMP 激活蛋白激酶（AMPK）激活介导的，IL-10 介导的对 SHRs VSMC 中 Ang II 诱导的增殖的抑制作用部分与 DDAH-1 有关。在这项研究中，我们研究了 exSulfs 对 IL-10 诱导的 DDAH-1 表达、Ang II 诱导的 DDAH-1 下调的抑制作用以及 Ang II 诱导的 SHRs VSMC 增殖的抑制作用。在转染 Sulf1 siRNA 的 SHRs VSMC 中，IL-10 诱导的 DDAH-1 表达和 Ang II 诱导的 DDAH-1 下调的抑制作用减弱。然而，Sulf2 并不影响 IL-10 诱导的 DDAH-1 表达和 Ang II 诱导的 DDAH-1 下调的抑制作用。Sulf1 的下调抑制了 IL-10 诱导的 AT R 表达以及 IL-10 对 Ang II 诱导的 AT R 表达的协同作用。此外，Sulf1 的下调抑制了 IL-10 诱导的 AMPK 活性以及 Ang II 诱导的 AMPK 活性下降。此外，在转染 Sulf1 siRNA 的 SHRs VSMC 中，没有检测到 IL-10 介导的对 Ang II 诱导的增殖的抑制作用；IL-10 介导的对 Ang II 诱导的 VSMC 增殖的抑制作用是通过 AT R 途径和 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 下调的抑制作用以及 Ang II 诱导的增殖的抑制作用，这些作用是通过 AT R 途径和 AMPK 激活介导的，主要是由 SHRs VSMC 中的 Sulf1 活性介导的。这些结果表明，在 SHRs VSMC 中，Sulf1（而不是 Sulf2）介导了 IL-10 对 Ang II 诱导的高血压作用的抑制。
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