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GW24-e2914 Involvement of vascular peroxidase 1 in the endothelial dysfunction in hypertension
  1. Shi RuiZheng1,
  2. Guogang Zhang2
  1. 1Department of Cardiovascular Medicine, Xiangya Hospital, Central South University
  2. 2Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham

Abstract

Objectives Vascular peroxidase 1 (VPO1) is a new heme-containing peroxidase, which can utilise hydrogen peroxide (H2O2) generated from co-expressed NADPH oxidase (NOX) to produce hypochlorous acid (HOCl) and catalyse peroxidative reactions. Our previous studies had found that NOX/VPO1 pathway-mediated oxidative stress plays an important role in myocardial ischaemia-reperfusion injury, endothelial cell apoptosis and/or smooth muscle cell proliferation. Considering the key role of the interaction between oxidative stress and endothelial dysfunction in causal mechanisms in hypertension. The aims of this study were to determine the potential role of VPO1 in endothelial dysfunction in hypertension.

Methods In the in vivo portion of thestudy, 20 weeks old Spontaneous hypertension rats (SHR) and Wistar-Kyoto rats were selected. The concentration-relaxation curve of aortic ring and the expression of VPO1 and endothelial nitric oxide synthase (eNOS) in arterial tissues were assessed; the nitric oxide (NO) level in plasma was measured. In the in vitro study, Human umbilical vein endothelial cells (HUVECs) were cultured and treated with angiotensin II, the eNOS expression and NO level were assessed while the expression of VPO1 and generation of H2O2 and HOCl were measured. Moreover, the effects of NOX inhibitor, the H2O2 scavenger, and the VPO1 inhibitor on the VPO1 expression, H2O2 and HOCl production were measured. Moreover, the direct effects of HOCl on eNOS expression and NO generation were also examined.

Results The VPO1 expression was significantly increased concomitantly with definite endothelial dysfunction in SHRs assessed by the substantial right shift of the concentration-relaxation curve, the decreased expression of eNOS in aortic ring and the decreased NO level in plasma. In cultured HUVECs we found that the angiotensin II-mediated down-regulation of eNOS expression and NO level was inhibited by knockdown of VPO1 using small hairpin RNA or the VPO1 specific inhibitor 4-aminobenzoic acid hydrazide. Moreover, the NADPH oxidase inhibitor and the hydrogen peroxide scavenger attenuated the angiotensin II-mediated up-regulation of VPO1 and HOCl generation. Furthermore, treatment with HOCl markedly decreased the eNOS expression and NO production.

Conclusions VPO1 is a novel regulator of endothelial dysfunction via NOX-H2O2-VPO1-HOCl-eNOS/NO pathways, which may contribute to the pathogenesis and/or development of hypertension.

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