Angiopoietin-1 aggravates atherosclerosis by inhibiting cholesterol efflux and promoting inflammatory response.

Abstract

OBJECTIVE:

Angiopoietin-1 (Ang-1), a secreted protein, mainly regulates angiogenesis. Ang-1 has been shown to promote the development of atherosclerosis, whereas little is known about its effects on lipid metabolism and inflammation in this process.

METHOD:

Ang-1 was transfected into ApoE-/- mice via lentiviral vector or incubated with THP-1 derived macrophages. Oil red O and HE staining were performed to measure the size of atherosclerotic plaques in ApoE-/- mice. Immunofluorescence was employed to show the expression of target proteins in aorta. [3H] labeled cholesterol was performed to examine the efficiency of cholesterol efflux and reverse cholesterol transport (RCT) both in vivo and vitro. Western blot and qPCR were used to quantify target proteins both in vivo and vitro. ELISA detected the levels of pro-inflammatory cytokines in mouse peritoneal macrophage.

RESULTS:

Our data showed that Ang-1 augmented atherosclerotic plaques formation and inhibited cholesterol efflux. The binding of Ang-1 to Tie2 resulted in downregulation of LXRα, ABCA1 and ABCG1 expression via inhibiting the translocation of TFE3 into nucleus. In addition, Ang-1 decreased serum HDL-C levels and reduced reverse cholesterol transport (RCT) in ApoE-/- mice. Furthermore, Ang-1 induced lipid accumulation followed by increasing TNF-α, IL-6, IL-1β，and MCP-1 produced by MPMs, as well as inducing M1 phenotype macrophage marker iNOS and CD86 expression in aorta of ApoE-/- mice.

CONCLUSION:

Ang-1 has an adverse effect on cholesterol efflux by decreasing the expression of ABCA1 and ABCG1 via Tie2/TFE3/LXRα pathway, thereby promoting inflammation and accelerating atherosclerosis progression.

• Authors: Xiang Ou, Jia-Hui Gao, Lin-Hao He, Xiao-Hua Yu, Gang Wang, Jin Zou, Zhen-Wang Zhao, Da-Wei Zhang, Zhi-Jiao Zhou, Chao-Ke Tang
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1865 Issue 2 Pg. 158535 (02 2020) ISSN: 1879-2618 [Electronic] Netherlands
• PMID: 31678621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• ABCA1 protein, human
• ABCG1 protein, human
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• Angiopoietin-1
• Angpt1 protein, mouse
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Liver X Receptors
• NR1H3 protein, human
• TFE3 protein, human
• Cholesterol
• Receptor, TIE-2
• Tek protein, mouse

Topics

• ATP Binding Cassette Transporter 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 1 (metabolism)
• Angiopoietin-1 (genetics, metabolism)
• Animals
• Atherosclerosis (immunology, metabolism, pathology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Cholesterol (metabolism)
• Disease Models, Animal
• Genetic Vectors (genetics)
• Humans
• Inflammation (immunology, metabolism, pathology)
• Lentivirus (genetics)
• Liver X Receptors (metabolism)
• Male
• Mice
• Mice, Knockout, ApoE
• Receptor, TIE-2 (metabolism)
• Signal Transduction (immunology)
• THP-1 Cells
• Transfection