NADPH oxidase 2-derived superoxide downregulates endothelial K(Ca)3.1 in preeclampsia

作者：Choi Shinkyu; Kim Ji Aee; Na Hye Young; Kim Ji Eun; Park Seonghee; Han Ki Hwan; Kim Young Ju; Suh Suk Hyo^*

来源：Free Radical Biology and Medicine, 2013, 57: 10-21.

DOI：10.1016/j.freeradbiomed.2012.12.009

• Hypertension
• Ca2+-activated K+ channel
• Anti-lectin-like oxidized low-density lipoprotein receptor 1
• NADPH oxidase
• Oxygen radicals
• Free radicals

Endothelial dysfunction is associated with K(Ca)3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial K(Ca)3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial K(Ca)3.1 dysfunction occurs in vessels from women with preeclampsia. We compared K(Ca)3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n=17) and preeclamptic pregnancy (PE; n=19) and examined the effects of plasma from NP or PE on K(Ca)3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial K(Ca)3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease. in K(Ca)3.1 current. Plasma from PE induced K(Ca)3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced K(Ca)3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert-butylhydroperoxide induced K(Ca)3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1-NOX2-mediated pathway and downregulates endothelial K(Ca)3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests K(Ca)3.1as a novel target for patients with preeclampsia.

• 出版日期2013-4