NDRG2 induced by oxidized LDL in macrophages antagonizes growth factor productions via selectively inhibiting ERK activation |
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Authors: | Shumei Liu Pengyuan Yang Hui Kang Ling Lu Yuefan Zhang Jingwei Pan Yao-Cheng Rui |
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Institution: | 1. Department of Pharmacology & School of Pharmacy, Second Military Medical University, Shanghai 200433, PR, China;2. Institute of Immunology & National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, PR, China;3. Department of Cardiology, Shanghai Jiaotong University Affiliated Sixth Peoples Hospital |
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Abstract: | During atherogenesis, macrophage foam cells produce prodigious growth factors, cytokines, and chemokines, which play the central roles in inflammatory process in atherosclerotic plaque formation. In the present study, we identified a new protein marker, N-Myc downstream-regulated protein 2 (NDRG2), which is significantly up-regulated in oxidized low density lipoprotein (oxLDL) treated macrophages and in human atherosclerotic plaques. Over-expression and siRNA knockdown studies showed that NDRG2 is a negative regulator of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) productions in macrophages. Furthermore, we investigated the effects of NDRG2 on MAPK signal activation. Our results showed ERK1/2 activation, but not P38 or JNK1/2 activation, is responsible for regulation of NDRG2 on VEGF and PDGF productions. Consistent with the PDGF levels, the vascular smooth muscle cell (VSMC) proliferation was also regulated by the conditional medium of the oxLDL treated macrophages with NDRG2 knockdown or over-expression. Neutralizing anti-PDGF antibody can significantly inhibit the enhanced VSMC proliferation by macrophage medium with NDRG2 knockdown. Our present results demonstrate that NDRG2 participates in oxLDL-induced macrophage activation and modulates ERK1/2-dependent PDGF and VEGF production, which has potential application in atherogenesis. |
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Keywords: | NDRG2 N-Myc downstream-regulated protein 2 VSMC vascular smooth muscle cell oxLDL oxidized low density lipoprotein PDGF platelet-derived growth factor VEGF vascular endothelial growth factor MAPK mitogen-activated protein kinase ERK extracellular signal-regulated kinases JNK/SAPK c-Jun N-terminal kinase/stress-activated protein kinases |
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