Abstract 3611: Atherogenic Role of the 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 activation product MAC has long been suspected, but is still unclear. Here, we demonstrate that among mice deficient in apolipoprotein E (Apoe) fed with a high fat diet (HFD) for either two or four months, the additional loss of murine CD59 (mCd59ab−/−/Apoe−/−) accelerated advanced atherosclerosis featuring occlusive coronary atherosclerosis associated with myocardial infarction, vulnerable plaque associated with plaque rupture, and premature death, and that these effect could be attenuated by selective over-expression of human CD59 in the endothelium, platelet and monocytes. Complement activation by the administration of cobra venom factor (30 μg/mouse, i.p. once per week for 3 week, and maintained the mice on HFD for one month) and complement inhibition using a neutralizing anti-mouse C5 antibody (40 mg/kg/day, i.p. on days 0 –2, followed by twice a week on days 3– 60 and maintained the mice on a HFD for 60 days.) respectively accelerated or prevented against atherosclerosis in mCd59ab−/−/Apoe−/− mice. Furthermore, we also documented that MAC mediated endothelial damage, promoted foam cell formation, and up-regulated the transcripts of pro-atherogenic growth factors and cytokines. These combined results highlight the atherogenic role of MAC and the athero-protective role of CD59, and suggest that inhibition of MAC formation may provide a therapeutic approach for the prevention and/or treatment of atherosclerosis.
This research has received full or partial funding support from the American Heart Association, AHA National Center.