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Updated: Mar 24, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice
Hui Liu1, Yanfei Xia1, Beibei Li1
1Qilu Hospital of Shandong University, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Jinan, Shandong 250012, China.
Insights
Prolyl hydroxylase domain-3 (PHD3) promotes atherosclerosis by increasing plaque size and inflammation. Inhibiting PHD3 reduces endothelial cell apoptosis, suggesting it as a therapeutic target for cardiovascular disease.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Pathophysiology
Background:
- Prolyl hydroxylase domain-3 (PHD3) is an iron-dependent dioxygenase regulating Hypoxia-inducible factor 1-alpha (HIF-1α).
- PHD3 expression is elevated in cardiovascular diseases, but its role in atherosclerosis remains unclear.
Purpose of the Study:
- To investigate the effect and mechanism of PHD3 in the development of atherosclerosis.
- To explore the role of PHD3 in endothelial cell apoptosis and inflammatory responses in vitro.
Main Methods:
- Apolipoprotein E-deficient (ApoE-/-) mice were treated with lentivirus to overexpress or inhibit PHD3.
- High-fat diet was administered to induce atherosclerosis.
- In vitro studies utilized human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL).
Main Results:
- PHD3 overexpression in ApoE-/- mice led to larger aortic atherosclerotic lesions, increased macrophage and smooth muscle cell infiltration, and enhanced plaque apoptosis.
- Overexpression of PHD3 upregulated inflammatory markers including ICAM-1, VCAM-1, MCP-1, IL-1β, and TNF-α.
- In vitro, PHD3 overexpression activated the MAPK signaling pathway (ERK1/2 and JNK), while PHD3 inhibition reduced ox-LDL-induced HUVEC apoptosis.
Conclusions:
- PHD3 plays a significant role in promoting atherogenesis, beyond its known function as an HIF-1α regulator.
- PHD3 contributes to atherosclerosis by exacerbating inflammation, cell infiltration, and apoptosis within atherosclerotic plaques.
- Targeting PHD3 may offer a therapeutic strategy for atherosclerosis by mitigating endothelial cell damage and inflammatory processes.
Abstract:
PHD3 belongs to the family of 2-oxoglutarate and iron-dependent dioxygenases and is a critical regulator of HIF-1α. 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-1beta (IL-1β) and tumor necrosis factor-α(TNF-α) 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 μg/ml). Our study suggests that PHD3 is not only a regulator of HIF-1α but also an active participant in atherogenesis.
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