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.
Keywords: Apoptosis; Atherosclerosis; MAPK; Prolyl hydroxylase 3.
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