Hypertensive effects of transforming growth factor-β1 in vascular smooth muscles cells from spontaneously hypertensive rats are mediated by sulfatase 2.

Abstract

Extracellular sulfatases (sulfatase 1 and sulfatase 2) mediate up- or down-regulatory effects of cytokines on angiotensin II (Ang II)-induced expression of hypertensive mediators in hypertensive cells. The overproduction of transforming growth factor-β1 (TGF-β1) is associated with chronic hypertension. In this study, we examined the role of extracellular sulfatases on TGF-β1-induced effects associated with the expression of mediators related to hypertension in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). First, TGF-β1 increased the expression of 12-lipoxygenase (12-LO) and endothelin-1 (ET-1), inhibited dimethylarginine dimethylaminohydrolase-1 (DDAH-1) expression and showed additive effects on Ang II-induced 12-LO and ET-1 expression as well as Ang II-induced inhibition of DDAH-1 expression in SHR VSMCs. However, it had no effect on the expression of 12-LO, ET-1, and DDAH-1 in VSMCs from normotensive Wistar Kyoto rats. Downregulation of sulfatase 2 (Sulf2) inhibited all of these hypertensive effects caused by TGF-β1, while sulfatase 1 (Sulf1) had no effect on these events in SHR VSMCs. All these hypertensive effects of TGF-β1 were dependent on the Ang II subtype 1 receptor (AT1 R) pathway, and not on Ang II subtype 2 receptor (AT2 R). In addition, downregulation of Sulf2 inhibited the expression of TGF-β1-induced AT1 R and the additive effect of TGF-β1 on Ang II-induced AT1 R expression. Additionally, downregulation of Sulf2, but not Sulf1, abrogated TGF-β1-induced inhibition of AMP-activated protein kinase (AMPK) activation and the additive effect of TGF-β1 on Ang II-induced inhibition of AMPK activation via the AT1 R pathway. Moreover, TGF-β1-induced VSMCs proliferation and the additive effect of TGF-β1 on Ang II-induced VSMCs proliferation were abrogated in Sulf2 siRNA-transfected SHR VSMCs, while these effects were maintained in Sulf1 siRNA-transfected SHR VSMCs. The hypertensive effects of TGF-β1 through the AT1 R pathway were mainly dependent on Sulf2 activity in SHR VSMCs. Taken together, these results suggest that Sulf2, but not Sulf1, plays a major role in mediating the increased effects of TGF-β1 in hypertensive VSMCs.