Peng Haiyang, Chen Luyao, Huang Xiao, Yang Tianlun, Yu Zaixin, Cheng Guangjie, Zhang Guogang, Shi Ruizheng
Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
J Am Soc Hypertens. 2016 Sep;10(9):741-751.e3. doi: 10.1016/j.jash.2016.06.036. Epub 2016 Jul 1.
Asymmetric dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase, contributes to endothelial dysfunction and subsequent cardiovascular events including hypertension. Vascular peroxidase 1 (VPO1) is a novel heme-containing peroxidase that uses hydrogen peroxide (H2O2) generated from co-expressed nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to catalyze peroxidative reactions. Our previous study revealed a clear connection between VPO1 gene expression and endothelial dysfunction in spontaneously hypertensive rats. In the present study, we explored whether VPO1 participates in endothelial dysfunction during hypertension by increasing ADMA production. Spontaneously hypertensive rats displayed impaired endothelium-dependent relaxation, decreased eNOS expression and nitric oxide production, significantly increased VPO1 expression in both plasma and aorta tissue, and an increased ADMA level in plasma. In cultured endothelial cells, angiotensin II increased the ADMA level by inhibiting dimethylarginine dimethylaminohydrolase activity, which was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor and the hydrogen peroxide scavenger attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid. Furthermore, VPO1-derived hypochlorous acid suppressed recombinant dimethylarginine dimethylaminohydrolase activity and increased ADMA production. VPO1 plays a critical role in ADMA production via H2O2-VPO1-hypochlorous acid pathways, which may contribute to endothelial dysfunction in hypertension.
不对称二甲基精氨酸（ADMA）是一氧化氮合酶的内源性抑制剂，可导致内皮功能障碍及后续心血管事件，包括高血压。血管过氧化物酶1（VPO1）是一种新型含血红素过氧化物酶，它利用共表达的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生的过氧化氢（H2O2）催化过氧化反应。我们之前的研究揭示了VPO1基因表达与自发性高血压大鼠内皮功能障碍之间存在明确联系。在本研究中，我们探讨了VPO1是否通过增加ADMA生成而参与高血压期间的内皮功能障碍。自发性高血压大鼠表现出内皮依赖性舒张受损、内皮型一氧化氮合酶（eNOS）表达及一氧化氮生成减少、血浆和主动脉组织中VPO1表达显著增加以及血浆中ADMA水平升高。在培养的内皮细胞中，血管紧张素II通过抑制二甲基精氨酸二甲胺水解酶活性增加ADMA水平，而使用小发夹RNA敲低VPO1可抑制这一作用。此外，NADPH氧化酶抑制剂和过氧化氢清除剂可减弱血管紧张素II介导的VPO1上调及次氯酸生成。此外，VPO1衍生的次氯酸抑制重组二甲基精氨酸二甲胺水解酶活性并增加ADMA生成。VPO1通过H2O2-VPO1-次氯酸途径在ADMA生成中起关键作用，这可能导致高血压中的内皮功能障碍。
