Role of VPO1, a newly identified heme-containing peroxidase, in ox-LDL induced endothelial cell apoptosis

Abstract

Myeloperoxidase (MPO) is an important enzyme involved in the genesis and development of atherosclerosis. Vascular peroxidase 1 (VPO1) is a newly discovered member of the peroxidase family that is mainly expressed in vascular endothelial cells and smooth muscle cells and has structural characteristics and biological activity similar to those of MPO. Our specific aims were to explore the effects of VPO1 on endothelial cell apoptosis induced by oxidized low-density lipoprotein (ox-LDL) and the underlying mechanisms. The results showed that ox-LDL induced endothelial cell apoptosis and the expression of VPO1 in endothelial cells in a concentration- and time-dependent manner concomitant with increased intracellular reactive oxygen species (ROS) and hypochlorous acid (HOCl) generation, and up-regulated protein expression of the NADPH oxidase gp91phox subunit and phosphorylation of p38 MAPK. All these effects of ox-LDL were inhibited by VPO1 gene silencing and NADPH oxidase gp91phox subunit gene silencing or by pretreatment with the NADPH oxidase inhibitor apocynin or diphenyliodonium. The p38 MAPK inhibitor SB203580 or the caspase-3 inhibitor DEVD-CHO significantly inhibited ox-LDL-induced endothelial cell apoptosis, but had no effect on intracellular ROS and HOCl generation or the expression of NADPH oxidase gp91phox subunit or VPO1. Collectively, these findings suggest for the first time that VPO1 plays a critical role in ox-LDL-induced endothelial cell apoptosis and that there is a positive feedback loop between VPO1/HOCl and the now-accepted dogma that the NADPH oxidase/ROS/p38 MAPK/caspase-3 pathway is involved in ox-LDL-induced endothelial cell apoptosis.

Activation of a7 Nicotinic Acetylcholine Receptor Protects Against Oxidant Stress Damage Through Reducing Vascular Peroxidase-1 in a JNK Signaling-Dependent Manner in Endothelial Cells

“…VPO-1 is a novel family member of peroxidases identified in cardiovascular system in 2008 [39]. VPO-1 is highly expressed in cardiomyocytes, endothelial cells and vascular smooth muscle cells [40,41,42], and thereby referred to vascular peroxidase (VPO). It is a glycosylated heme-peroxidase that is actively secreted into circulating plasma by vascular endothelial cells [39].…”

Reactive Oxygen Species

“…However, in the disease states, overproduction of hypohalous acids by these enzymes may have pathogenic consequences. Indeed, activation of MPO and overproduction of HOCl has been reported in diabetes [16] and peroxidasin has been shown to mediate oxidative vascular damage and renal fibrosis [17][18][19][20]. Increase in HOCl-derived protein oxidation has been reported in renal tissues of patients with chronic kidney disease [14,21].…”

Role of vascular peroxidase 1 in senescence of endothelial cells in diabetes rats

“…It is mainly expressed in vascular wall, liver and lung while MPO exists only in neutrophils, monocytes and macrophages [9]. However, as same as MPO, VPO1 is capable to catalyze H 2 O 2 and chloride to produce HOCl [10]. In our laboratory, we have identified that VPO1 pathogenically contributes to several cardiovascular diseases including hypertension, atherosclerosis and coronary heart disease.…”

“…In our laboratory, we have identified that VPO1 pathogenically contributes to several cardiovascular diseases including hypertension, atherosclerosis and coronary heart disease. It has been shown that Angtension II and ox-LDL, which can induce oxidative stress, significantly upregulates VPO1 expression in vascular smooth muscle cells or endothelial cells [10][11][12]. According as generation of ROS induced by hyperglycemia, it is likely that VPO1/HOCl pathway is involved in senescence of endothelial cells in diabetes mellitus.…”