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.
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.
Authors: Sotirios Tsimikas; Atsushi Miyanohara; Karsten Hartvigsen; Esther Merki; Peter X Shaw; Meng-Yun Chou; Jennifer Pattison; Michael Torzewski; Janina Sollors; Theodore Friedmann; N Chin Lai; H Kirk Hammond; Godfrey S Getz; Catherine A Reardon; Andrew C Li; Carole L Banka; Joseph L Witztum Journal: J Am Coll Cardiol Date: 2011-10-11 Impact factor: 24.094
Authors: Iris Müller; Tanja Schönberger; Martina Schneider; Oliver Borst; Melanie Ziegler; Peter Seizer; Christoph Leder; Karin Müller; Michael Lang; Florian Appenzeller; Oleg Lunov; Berthold Büchele; Manuela Fahrleitner; Marcus Olbrich; Harald Langer; Tobias Geisler; Florian Lang; Madhumita Chatterjee; Jan Freark de Boer; Uwe J F Tietge; Jürgen Bernhagen; Thomas Simmet; Meinrad Gawaz Journal: J Biol Chem Date: 2013-09-03 Impact factor: 5.157
Authors: René R Sevag Packard; XiaoXiao Zhang; Yuan Luo; Teng Ma; Nelson Jen; Jianguo Ma; Linda L Demer; Qifa Zhou; James W Sayre; Rongsong Li; Yu-Chong Tai; Tzung K Hsiai Journal: Ann Biomed Eng Date: 2016-02-08 Impact factor: 3.934