Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

• Published in: Circulation research 2011-03, Vol.108 (6), p.695-703
• Main Authors: Zeibig, Stephan, Li, Zhongmin, Wagner, Silvia, Holthoff, Hans-Peter, Ungerer, Martin, Bültmann, Andreas, Uhland, Kerstin, Vogelmann, Jasmin, Simmet, Thomas, Gawaz, Meinrad, Münch, Götz
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, Differentiation, Myelomonocytic - genetics; Aorta - drug effects; Aorta - pathology; Apolipoproteins E - deficiency; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - pathology; Binding, Competitive; Biological and medical sciences; Blood and lymphatic vessels; Brachiocephalic Trunk - drug effects; Brachiocephalic Trunk - pathology; Cardiology. Vascular system; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Collagen - metabolism; Disease Progression; Fundamental and applied biological sciences. Psychology; Humans; Immunoglobulin Fc Fragments - genetics; Inflammation - metabolism; Inflammation - pathology; Lipid Metabolism; Lipoproteins, LDL - metabolism; Macrophages - pathology; Male; Medical sciences; Mice; Mice, Knockout; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; T-Lymphocytes - pathology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.240515

RATIONALE:There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and that oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques. OBJECTIVE:To block oxLDL, we designed, expressed, and tested Fc-CD68, a soluble oxLDL binding protein consisting of human Fc and the extracellular domain of the human oxLDL-binding receptor CD68. METHODS AND RESULTS:Fc-CD68 bound with high specific affinity to oxLDL and strongly bound and colocalized with oxLDL in plaques. To study the effects of repeated administrations of Fc-CD68 on the progression of atherosclerosis and plaque vulnerability, 12- and 16-week old cholesterol-fed ApoE mice received either Fc-CD68 (n=6) or Fc control protein (n=6 to 8) thrice weekly for 4 weeks. Macroscopic and histological analysis of Sudan red lipid staining showed strong and significant reduction of plaque extension in the aorta and in the aortic root, respectively. Histological analysis of pentachrome- and Sirius-stained sections of the brachiocephalic arteries of 20 week-old ApoE mice revealed that Fc-CD68 significantly reduced the occurrence of spontaneous ruptures of established plaques by ≈20%, compared with Fc and drastically increased the collagen content of plaques. Furthermore, in immunostained sections of the brachiocephalic artery and the aortic root, Fc-CD68 reduced the infiltration of plaques with T lymphocytes, and macrophages by ≈50% and 30%, respectively. CONCLUSIONS:The oxLDL binding protein Fc-CD68 attenuates atherosclerosis and strengthens the stability of atherosclerotic plaques.