Coiled-coil domain-containing 80 accelerates atherosclerosis development through decreasing lipoprotein lipase expression via ERK1/2 phosphorylation and TET2 expression.

Abstract

Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin-eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2-regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis.

• Authors: Duo Gong, Qiang Zhang, Ling-Yan Chen, Xiao-Hua Yu, Gang Wang, Jin Zou, Xi-Long Zheng, Da-Wei Zhang, Wei-Dong Yin, Chao-Ke Tang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 843 Pg. 177-189 (Jan 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30439364 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Ccdc80 protein, mouse
• DNA-Binding Proteins
• Extracellular Matrix Proteins
• Forkhead Box Protein O3
• FoxO3 protein, mouse
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins
• Triglycerides
• Dioxygenases
• Tet2 protein, mouse
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Lipoprotein Lipase

Topics

• Animals
• Atherosclerosis (metabolism)
• DNA Methylation
• DNA-Binding Proteins (metabolism)
• Dioxygenases
• Extracellular Matrix Proteins
• Forkhead Box Protein O3 (metabolism)
• Glycoproteins (metabolism)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Lipoprotein Lipase (genetics, metabolism)
• Male
• Mice, Knockout, ApoE
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins (metabolism)
• Triglycerides (blood)