title: Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice.
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.
authors.affiliation: Qilu 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Qilu 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.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Qilu 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.
authors.forename: Beibei
authors.initials: B
authors.lastname: Li
authors.affiliation: Qilu 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.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Pan
authors.affiliation: Qilu 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.
authors.forename: Mei
authors.initials: M
authors.lastname: Lv
authors.affiliation: Qilu 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.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Qilu 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. Electronic address: anfengshuang1028@sina.com.
authors.forename: Fengshuang
authors.initials: F
authors.lastname: An
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C573420:ICAM1 protein, human; C508585:IL1B protein, human; C587672:IL1B protein, mouse; C090509:Icam1 protein, mouse; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase
keywords: Apoptosis; Atherosclerosis; MAPK; Prolyl hydroxylase 3