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From the British Heart Foundation Cardiovascular Medicine Unit,* Vascular Science Section, National Heart and Lung Institute, Imperial College, London; Department of Histopathology, Hammersmith Hospital, London; Atherosclerosis Department, GlaxoSmithKline, Stevenage; and Rheumatology Unit, Division of Medicine, Imperial College, London, United Kingdom
We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa–/–) with low-density lipoprotein receptor knockout mice (Ldlr–/–). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa–/–/Ldlr–/– mice compared with Ldlr–/– mice (3.72 ± 1.0% aortic root versus 1.1 ± 0.4%; mean ± SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa–/–/Ldlr–/– was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa–/–/Ldlr–/– mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa–/–/Ldlr–/–, whereas apoptotic cells were not detected in Ldlr–/– mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa–/–/Ldlr–/– mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.
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