The role of complement in atherosclerosis

There is increasing evidence that the complement system plays a role in atherosclerosis, although its exact functions in the vessel wall are still unclear (1, 2). Complement components, including C3 activation products and C5b-9, can be detected immunohistochemically in atherosclerotic plaques (3-6). In rabbits, C5b-9 deposition occurs at an early stage of atherogenesis in conjunction with cholesterol accumulation (7). Interestingly, in established human atherosclerosis, C5b-9 is seen particularly in relation to vascular smooth muscle cells (VSMC) surface membranes and is more prominent in fibrous plaques than in fatty streaks (6, 8, 9). Although complement activation might be expected to exacerbate atherosclerosis via the pro-inflammatory effects of C3a, C5a, and C5b-9, it has recently become clear that the classical pathway and inactivated C3b may also be protective through opsonising debris such as apoptotic cells and contributing to non-inflammatory clearance by macrophages (10, 11).

Previous studies using complement deficient animals have provided apparently contradictory conclusions. In rabbits, C6 deficiency protects against diet-induced atherosclerosis, supporting an important role for the terminal pathway (12, 13). Patel and colleagues have studied the effect of crossing spontaneous C5 deficient mice with  ApoE-/- mice (14). No difference in lesion size was observed after 22 weeks on a high fat diet. However, by 22 weeks lesions in ApoE-/- mice are well advanced and earlier time-points were not examined. C3 deficient LDLR-/- mice have been shown to have increased aortic lipid deposition after 15 weeks on a high fat diet, with an apparent failure of fatty steaks to develop into fibrotic lesions 15. It should be noted that this study investigated mice on a mixed 129Sv x C57BL/6 genetic background, which might give a different phenotype to a pure C57BL/6 background.  More recently, Persson et al have reported an increase in aortic lesion area in 16 week old chow-fed C3 deficient mice crossed with LDLR-/- ApoE-/- double deficient mice, although interpretation of the results was complicated by  C3 deficiency being associated with a more atherogenic lipid profile and reduced body weight (16). In the same study, Factor B deficiency had no effect on atherosclerosis, suggesting that the alternative pathway is not critical.

We have introduced the low density lipoprotein receptor knockout mouse (ldlr-/-) model of atherosclerosis into the group with a view to analyzing the role of the complement system in more detail, making use of in-house knock-out strains.   The work is funded by a BHF Programme Grant.

References

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