Vascular VPO1 expression is related to the endothelial dysfunction in spontaneously hypertensive rats.

Reactive oxygen species (ROS) contributes to endothelial dysfunction that is involved in the pathogeneses of hypertension. Vascular peroxidase 1 (VPO1) can utilize ROS to catalyze peroxidative reactions, possibly enhancing endothelial dysfunction. This study is to identify VPO1's involvement in endothelial dysfunction and hypertension. Sixty-four spontaneously hypertensive rats (SHRs) and 64 age-matched, bodyweight controlled normotensive Wistar-Kyoto rats (WKYs) were randomly grouped and studied at the age of 5, 8, 13 and 20 weeks (16 animals, each). Blood pressure and vasodilator responses to acetylcholine in aortic rings were observed. The expressions of VPO1 and endothelial NO synthase (eNOS) in aortas were assessed by quantitative reverse transcription-PCR and western blotting analysis. Plasma concentrations of hydrogen peroxide (H2O2) and NO, NOX activity, hypochlorous acid (HOCl) production, and 3-nitrotyrosine content in aortic homogenates were also determined in this study. Along with the development of hypertension in SHR rats, VPO1 expression was up-regulated together with a significant increase in NOX activity, HOCl production, 3-nitrotyrosine content, and plasma H2O2 level compared with WKYs at 8, 13 and 20 weeks of age. In contrast, blood NO levels were decreased and aortic relaxation to acetylcholine was deteriorated in SHRs. The over-expression of VPO1 during the development of hypertension, accompanied by the endothelial dysfunction, the decreased NO levels, the elevated NOX and ROS activities, indicates a clear connection between VPO1 gene and hypertension. VPO1 may pathogenetically contribute to hypertension via signal pathways involving NOX-H2O2-VPO1-HOCl or JNK/p38 MAPK although further studies are needed to determine the precise mechanisms.

Yang L ，Bai Y ，Li N ，Hu C ，Peng J ，Cheng G ，Zhang G ，Shi R ... -  《-》

A novel pathway of NADPH oxidase/vascular peroxidase 1 in mediating oxidative injury following ischemia-reperfusion.

Zhang YS ，He L ，Liu B ，Li NS ，Luo XJ ，Hu CP ，Ma QL ，Zhang GG ，Li YJ ，Peng J ... -  《-》

Involvement of vascular peroxidase 1 in angiotensin II-induced hypertrophy of H9c2 cells.

Oxidative stress has been implicated in cardiac hypertrophy and heart failure. Vascular peroxidase 1 (VPO1), a peroxidase in the cardiovascular system, uses the hydrogen peroxide (H2O2) derived from co-expressed NADPH oxidases (NOX) to produce hypochlorous acid (HOCl) and catalyze peroxidative reactions. Our previous studies showed that VPO1 contributes to the vascular smooth muscle cell proliferation and endothelial dysfunction in spontaneous hypertensive rats (SHRs); however, the role of VPO1 in cardiomyocytes hypertrophy is still uninvestigated. The present study was therefore undertaken to examine the role of VPO1 in the angiotensin II-induced cardiac hypertrophy, and the underlying mechanism by which VPO1 regulates the redox signaling. As compared to WKY rats, the SHRs exhibited increased myocyte cross sectional area, enhanced Nox2 and VPO1 expression level in cardiac tissue, and an increased Ang II level in plasma. In cultured H9c2 cell line, Ang II increased the hypertrophy-related gene (BNP/ANF) expression and the cellular surface area, which was attenuated by knocking down of VPO1 via VPO1 siRNA or pharmacological inhibition of NOX/VPO1 pathway. Moreover, the enhanced hypochlorous acid (HOCl) production and phosphorylation of ERK1/2 was suppressed by VPO1 knockdown. Furthermore, the protective role of VPO1 siRNA transfection on H9c2 cardiomyocytes hypertrophy was abrogated on the HOCl stimulation, and the phosphorylated ERK1/2 expression level was found also upregulated after HOCl stimulation. In conclusion, these results suggest that the Nox2/VPO1/HOCl/ERK1/2 redox signaling pathway was implicated in the pathogenesis of Ang II-induced cardiac hypertrophy.

Yang W ，Liu Z ，Xu Q ，Peng H ，Chen L ，Huang X ，Yang T ，Yu Z ，Cheng G ，Zhang G ，Shi R ... -  《-》

Vascular peroxidase 1 up regulation by angiotensin II attenuates nitric oxide production through increasing asymmetrical dimethylarginine in HUVECs.

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.

Peng H ，Chen L ，Huang X ，Yang T ，Yu Z ，Cheng G ，Zhang G ，Shi R ... -  《-》

The role of vascular peroxidase 1 in ox-LDL-induced vascular smooth muscle cell calcification.

Reactive oxygen species (ROS)-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) is associated with the pathogenesis of vascular calcification. Vascular peroxidase 1 (VPO1), a peroxidase in the cardiovascular system, utilizes the hydrogen peroxide (H2O2) produced by co-expressed NADPH oxidases to produce hypochlorous acid (HOCl) and catalyze peroxidative reactions. The aim of this study was to determine whether VPO1 plays a role in the osteogenic differentiation of VSMCs in the setting of the vascular calcification induced by oxidized low-density lipoprotein (ox-LDL). In cultured primary rat VSMCs, we observed that the expression of VPO1 was significantly increased in combination with increases in calcification, as demonstrated via increased mineralization, as well as increased alkaline phosphatase (ALP) activity and up-regulated runt-related transcription factor 2 (Runx2) expression in ox-LDL-treated cells. Ox-LDL-induced VSMC calcification and Runx2 expression were both inhibited by knockdown of VPO1 using a small interfering RNA or by an NADPH oxidase inhibitor. Moreover, the knockdown of VPO1 in VSMCs suppressed the production of HOCl and the phosphorylation of AKT, ERK and P38 MAPK. Furthermore, HOCl treatment facilitated the phosphorylation of AKT, ERK1/2 and P38 MAPK and the expression of Runx2, whereas LY294002 (a specific inhibitor of PI3K), U0126 (a specific inhibitor of ERK1/2) and SB203580 (a specific inhibitor of P38 MAPK) significantly attenuated the HOCl-induced up-regulation of Runx2. Collectively, these results demonstrated that VPO1 promotes ox-LDL-induced VSMC calcification via the VPO1/HOCl/PI3K/AKT, ERK1/2, and P38 MAPK/Runx2 signaling pathways.

Tang Y ，Xu Q ，Peng H ，Liu Z ，Yang T ，Yu Z ，Cheng G ，Li X ，Zhang G ，Shi R ... -  《-》