Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex.
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.
Wu
Gongxiong
G
Department of Medicine, Brigham and Women's Hospital, Laboratory forTranslational Research, Harvard Medical School, Cambridge, MA 02139, USA.
Hu
Weiguo
W
Shahsafaei
Aliakbar
A
Song
Wenping
W
Dobarro
Martin
M
Sukhova
Galina K
GK
Bronson
Rod R
RR
Shi
Guo-Ping
GP
Rother
Russell P
RP
Halperin
Jose A
JA
Qin
Xuebin
X
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003167:Complement Activation; D003182:Complement C5 / Q000276:immunology; D003186:Complement C9 / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D003324:Coronary Artery Disease / Q000276:immunology / Q000517:prevention & control; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D005487:Foam Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011817:Rabbits; D012720:Severity of Illness Index; D013997:Time Factors
D001057:Apolipoproteins E; D018957:CD59 Antigens; D003182:Complement C5; D003186:Complement C9; D015938:Complement Membrane Attack Complex; D004041:Dietary Fats; C051590:CD59 protein, human