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Overexpression of Angiopoietin-Like Protein 4 Protects Against Atherosclerosis Development

Author: Georgiadi, A. · Wang, Y. · Stienstra, R. · Tjeerdema, N. · Janssen, A. · Stalenhoef, A. · Vliet, J.A. van der · Roos, A. de · Tamsma, J.T. · Smit, J.W. · Tan, N.S. · Müller, M. · Rensen, P.C. · Kersten, S.
Source:Arteriosclerosis, Thrombosis and Vascular Biology, 33, 1529-1537
Identifier: 525800
doi: DOI:10.1161/ATVBAHA.113.301698
Keywords: Health · Atherosclerosis · Inflammation · Lipoprotein lipase · Lipoproteins · Macrophages · Food and Nutrition · Healthy Living · Life · MHR - Metabolic Health Research · EELS - Earth, Environmental and Life Sciences


Objective: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. Approach and Results: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (−41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (−37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. Conclusions: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.