Fn14-Fc Fusion Protein Regulates Atherosclerosis in ApoE−/− Mice and Inhibits Macrophage Lipid Uptake In Vitro

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 29; no. 12; pp. 2021 - 2027
• Main Authors: Schapira, Kitty, Burkly, Linda C, Zheng, Timothy S, Wu, Ping, Groeneweg, Mathijs, Rousch, Mat, Kockx, Mark M, Daemen, Mat J.A.P, Heeneman, Sylvia
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2009; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apoptosis - drug effects; Apoptosis - physiology; Atherosclerosis (general aspects, experimental research); Atherosclerosis - drug therapy; Atherosclerosis - etiology; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Biological and medical sciences; Biological Transport, Active - drug effects; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Movement - drug effects; Cell Movement - physiology; Cytokine TWEAK; Cytokines - biosynthesis; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; General and cellular metabolism. Vitamins; In Vitro Techniques; Lipid Metabolism - drug effects; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Receptors, Tumor Necrosis Factor - physiology; Recombinant Fusion Proteins - pharmacology; Tumor Necrosis Factors - antagonists & inhibitors; Tumor Necrosis Factors - physiology; TWEAK Receptor; TWEAK; Rodentia; Cardiovascular disease; Fn14; mice; Uptake; Vascular disease; Vertebrata; macrophages; Mammalia; Mouse; Animal; Atherosclerosis; ApoE; Fusion protein; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.109.195040

OBJECTIVE—TWEAK is a multifunctional cytokine belonging to the tumor necrosis factor superfamily and binds to the receptor Fn14. TWEAK and Fn14 are expressed in atherosclerotic plaques in areas rich in macrophages and foam cells. We investigated the role of TWEAK/Fn14 interactions in ApoE mice and bone marrow–derived macrophages in vitro. METHODS AND RESULTS—ApoE mice were treated with TWEAK-inhibiting fusion protein, Fn14-Fc, in an early (5 to 17 weeks of age) or delayed (17 to 29 weeks of age) setting. In the aortic arch, Fn14-Fc as compared to control treatment resulted in advanced plaques which were smaller (early treatment), fewer (delayed treatment), lower in fibrotic content (early and delayed treatment), and exhibited an increased macrophage content and smaller macrophage size (delayed treatment). There were no differences in apoptosis in atherosclerotic plaques after Fn14-Fc versus control Ab treatment. However, blocking TWEAK resulted in less macrophage uptake of modified lipids in vitro. CONCLUSIONS—Fn14-Fc fusion protein treatment did not prevent lesion initiation but inhibited some features of plaque progression and induced a unique advanced plaque phenotype with increased macrophage content and smaller macrophage size, which may be attributable to reduced lipid uptake. These findings indicate that TWEAK/Fn14 interactions regulate atherosclerosis and mediate lipid uptake in macrophages.