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Published on: August 20, 2019
Angiopoietin-1 aggravates atherosclerosis by inhibiting cholesterol efflux and promoting inflammatory response
Xiang Ou1, Jia-Hui Gao2, Lin-Hao He3
1Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; Department of Endocrinology, The First Hospital of Changsha, Changsha, Hunan 410005, China.
Insights
Angiopoietin-1 (Ang-1) worsens atherosclerosis by inhibiting cholesterol efflux through the Tie2/TFE3/LXRα pathway, increasing inflammation and plaque formation in ApoE-/- mice.
Area of Science:
- Cardiovascular Biology
- Lipid Metabolism
- Atherosclerosis Research
Background:
- Angiopoietin-1 (Ang-1) is a secreted protein primarily regulating angiogenesis.
- While Ang-1 promotes atherosclerosis, its specific impact on lipid metabolism and inflammation in this context is not well understood.
Purpose of the Study:
- To investigate the effects of Angiopoietin-1 on lipid metabolism, inflammation, and atherosclerosis progression.
- To elucidate the molecular mechanisms underlying Ang-1's influence on cholesterol efflux and plaque development.
Main Methods:
- ApoE-/- mice were treated with Ang-1 via lentiviral vectors; THP-1 derived macrophages were also used.
- Assessed atherosclerotic plaque size, cholesterol efflux, reverse cholesterol transport (RCT), and inflammatory cytokine levels.
- Utilized Oil red O, HE staining, immunofluorescence, [3H]-cholesterol assays, Western blot, qPCR, and ELISA.
Main Results:
- Ang-1 significantly augmented atherosclerotic plaque formation and inhibited cholesterol efflux.
- Ang-1 downregulated LXRα, ABCA1, and ABCG1 expression via the Tie2/TFE3 pathway, reducing HDL-C and RCT.
- Ang-1 promoted lipid accumulation, increased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1), and induced M1 macrophage markers.
Conclusions:
- Angiopoietin-1 adversely affects cholesterol efflux by decreasing ABCA1 and ABCG1 expression through the Tie2/TFE3/LXRα pathway.
- This mechanism promotes inflammation and accelerates atherosclerosis progression.
- Ang-1 plays a detrimental role in cardiovascular health by exacerbating lipid dysregulation and inflammatory responses in atherosclerosis.
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.
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