Published online before print January 8, 2009, doi: 10.1161/CIRCRESAHA.108.191361
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 17, 2008
Revised on December 19, 2008
Accepted on December 30, 2008
Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex
Gongxiong Wu ;
From the Department of Medicine (G.W., W.H., A.S., W.S., M.D., J.A.H., X.Q.), Brigham and Women's Hospital, Boston, Mass; Laboratory for Translational Research (G.W., W.H., J.A.H., X.Q.), Harvard Medical School, Cambridge, Mass; Department of Medical Neurobiology & Neuroanatomy (G.W.), Medical School of Sun Yat-sen University, Guangzhou, Guangdong, Peoples Republic of China; Department of Medicine (G.K.S., G.-p.S.), Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Mass; Rodent Histopathology Core (R.R.B.), Dana Farber/Harvard University Medical School, Boston, Mass; and Alexion Pharmaceuticals Inc (R.P.R.), Cheshire, Conn.
* To whom correspondence should be addressed. E-mail: xuebin_qin{at}hms.harvard.edu.
Complement is a central effector system within the immune system and is implicated in a range of inflammatory disorders. CD59 is a key regulator of complement membrane attack complex (MAC) assembly. The atherogenic role of terminal complement has long been suspected but is still unclear. Here, we demonstrate that among mice deficient in apolipoprotein (Apo)E, the additional loss of murine CD59 (mCd59ab-/-/ApoE-/-) accelerated advanced atherosclerosis featuring occlusive coronary atherosclerosis, vulnerable plaque, and premature death and that these effect could be attenuated by overexpression of human CD59 in the endothelium. Complement inhibition using a neutralizing anti-mouse C5 antibody attenuated atherosclerosis in mCd59ab-/-/ApoE-/- mice. Furthermore, MAC mediated endothelial damage and promoted foam cell formation. These combined results highlight the atherogenic role of MAC and the atheroprotective role of CD59 and suggest that inhibition of MAC formation may provide a therapeutic approach for the treatment of atherosclerosis.
Key words: CD59 • complement • complement regulation • endothelial dysfunction • atherosclerosis • occlusive coronary atherosclerosis and vulnerable plaque
This article has been cited by other articles:
 |
|
 |
|
  V. W.Y. Leung, S. Yun, M. Botto, J. C. Mason, T. H. Malik, W. Song, D. Paixao-Cavalcante, M. C. Pickering, J. J. Boyle, and D. O. Haskard Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Am. J. Pathol., October 1, 2009; 175(4): 1757 - 1767. [Abstract] [Full Text] [PDF]
|
|