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Published on: August 20, 2019
Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and
Eiji Horio1, Tsuyoshi Kadomatsu, Keishi Miyata
1From the Department of Molecular Genetics (E.H., T.K., K.M., H.H., M.E., M. Tabata, H.T., Z.T., O.T., K.T., Y.O.), Department of Cardiovascular Medicine (E.H., H.O., K.K.), and Department of Cell Pathology (M. Takeya), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Division of Geriatric Medicine, Department of Internal Medicine (Y.A., N.H.) and Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine (K.H., T.S.), Keio University School of Medicine, Tokyo, Japan; Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Y.D., T.N., Y.K.); Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan (H.H.); Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan (T.M.); and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (Y.O.).
Insights
Angiopoietin-like protein 2 (Angptl2) drives vascular inflammation and atherosclerosis progression. Reducing Angptl2 in endothelial cells can attenuate this process, offering potential therapeutic targets for cardiovascular disease.
Area of Science:
- Cardiovascular biology
- Immunology
- Molecular medicine
Background:
- Cardiovascular disease (CVD) is a leading cause of death, often driven by atherosclerosis.
- Vascular inflammation is a critical pathology in atherosclerosis, but its molecular drivers are not fully understood.
- Angiopoietin-like protein 2 (Angptl2) is a known proinflammatory protein.
Purpose of the Study:
- To investigate the role of angiopoietin-like protein 2 (Angptl2) in vascular inflammation and atherosclerosis progression.
- To determine if Angptl2 contributes to the development of cardiovascular disease.
Main Methods:
- Histological analysis of human cardiovascular disease patient samples.
- Atherosclerosis studies in angiopoietin-like protein 2 (Angptl2) knockout and transgenic mice (ApoE(-/-)/Angptl2(-/-)), and bone marrow transplantation.
- In vitro studies using endothelial cells and macrophages.
Main Results:
- Angiopoietin-like protein 2 (Angptl2) is highly expressed in atherosclerotic plaques.
- Angptl2 knockout attenuated atherosclerosis by reducing macrophage infiltration and vascular inflammation.
- Endothelial cell-specific Angptl2 expression accelerated plaque formation and caused endothelial dysfunction.
Conclusions:
- Endothelial cell-derived Angptl2 promotes vascular inflammation and atherosclerosis progression.
- Angptl2 activates proinflammatory signaling in endothelial cells and enhances macrophage recruitment.
- Targeting Angptl2 may offer a therapeutic strategy for cardiovascular disease.
Objective:
Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression.
Approach And Results:
Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE(-/-)/Angptl2(-/-)) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE(-/-) mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE(-/-)/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2(-/-) mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis.
Conclusions:
Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
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