Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice
Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice
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脯氨酰羟化酶 3 过度表达会加速 ApoE-/- 小鼠动脉粥样硬化的进展。
DOI：
10.1016/j.bbrc.2016.03.058
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发表时间：
2016-04-22
影响因子：
3.1
通讯作者：
An, Fengshuang
中科院分区：
文献类型：
--
作者：
Liu, Hui;Xia, Yanfei;An, Fengshuang
PHD3 属于 2-酮戊二酸和铁依赖性双加氧酶家族，是 HIF-1α 的关键调节因子。其表达在心肌病、心肌缺血再灌注损伤、充血性心力衰竭等心血管疾病中升高。然而，PHD3与动脉粥样硬化之间的关联尚未明确阐明。在本研究中，我们研究了PHD3对载脂蛋白E缺陷(ApoE/)小鼠的潜在作用和机制。构建鼠PHD3慢病毒和shRNA PHD3慢病毒并静脉注射至高脂饮食喂养的ApoE/小鼠中。 PHD3过表达时主动脉粥样硬化病变面积更大。随着 PHD3 水平的增加，巨噬细胞和平滑肌细胞得到增强。当 PHD3 升高时，动脉粥样硬化斑块的凋亡增加。此外，细胞间细胞粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）、单核细胞趋化蛋白1（MCP -1）、白细胞介素-iβ（IL-1（3））和肿瘤坏死因子-α（TNF-α）的表达随着PHD3的过表达而上调。在体外，我们探索了PHD3在HUVEC中的特异性信号通路。PHD3过表达与激活相关。 PHD3 信号通路的 ERK1/2 和 JNK 磷酸化降低了 ox-LDL（50 50 μg/ml）处理的 HUVEC 的凋亡。我们的研究表明，PHD3 不仅是 HIF-1 α 的调节剂，而且是动脉粥样硬化形成的积极参与者。保留所有权利。
PHD3 belongs to the family of 2-oxoglutarate and iron -dependent dioxygenases and is a critical regulator of HIF-la. Its expression is increased in cardiovascular diseases such as cardiomyopathy, myocardial ischemia-reperfusion injury, and congestive heart failure. However, the association between PHD3 and atherosclerosis has not been clearly elucidated. In the present study, we investigated the potential effect and mechanism of PHD3 in apolipoprotein E deficient (ApoE /) mice. Murine PHD3 lentivirus and shRNA PHD3 lentivirus were constructed and injected intravenously into ApoE / mice fed on a high fat diet. The aortic atherosclerotic lesion area was larger with PHD3 over-expression. With increased PHD3 levels, macrophages and smooth muscle cells were enhanced. The apoptosis of atherosclerotic plaques revealed an increase when PHD3 was elevated. Furthermore, the expression of intercellular cell adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), monocyte chemotactic protein 1 (MCP -1), interleukin-i beta (IL-1(3) and tumor necrosis factor-alpha(TNF-alpha) were upregulated with PHD3 over-expression. In vitro, we explored the specific signaling pathway of PHD3 in HUVECs. PHD3 over-expression is associated with activation of ERK1/2 and JNK phosphorylation of MAPK signaling pathway. PHD3 inhibition decreased the apoptosis of HUVECs treated with ox-LDL (50 50 mu g/ml). Our study suggests that PHD3 is not only a regulator of HIF-1 alpha but also an active participant in atherogenesis. (C) 2016 Elsevier Inc. All rights reserved.