ApoE−/− Mice Develop Atherosclerosis in the Absence of Complement Component C5

Patel, Sushma; Thelander, Erin M.; Hernandez, Melba; Montenegro, Judy; Hassing, Heide; Burton, Charlotte; Mundt, Steven S.; Hermanowski‐Vosatka, Anne; Wright, Samuel D.; Chao, Yu‐Sheng; Detmers, Patricia A.

doi:10.1006/bbrc.2001.5276

Cited by 62 publications

(60 citation statements)

References 24 publications

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“…46 Last, Patel and colleagues found no effect of reduced downstream complement activity because of C5 deficiency in ApoE Ϫ/Ϫ mice. 47 A role for the MBL pathway in mouse atherosclerosis remains possible, given the in- A: Low magnification for orientation. L, lumen.…”

Section: Discussionmentioning

confidence: 99%

Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Bhatia

Yun

Leung

et al. 2007

The American Journal of Pathology

144

125

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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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Section: Discussionmentioning

confidence: 99%

Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Bhatia

Yun

Leung

et al. 2007

The American Journal of Pathology

144

125

View full text Add to dashboard Cite

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“…We have confirmed that human CRP complexed with its highest affinity ligand, C-polysaccharide, does activate C3 in mouse serum (results not shown), but the effects of human CRP binding to potentially important endogenous murine ligands (such as lipoproteins, apoptotic cells, and cellular debris) are not known. Also, mouse complement C5-9 has much lower activity than the human terminal sequence and is not required for atherogenesis in apoE knockout mice (54). Therefore, any extrapolation to human pathophysiology from this or similar models must be guarded.…”

Section: Discussionmentioning

confidence: 99%

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

Hirschfield

Gallimore

Kahan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

178

123

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The association between circulating concentrations of C-reactive protein (CRP) and future atherothrombotic events has provoked speculation about a possible pathogenetic role of CRP. However, we show here that transgenic expression of human CRP had no effect on development, progression, or severity of spontaneous atherosclerosis, or on morbidity or mortality, in male apolipoprotein E (apoE)-deficient C57BL͞6 mice up to 56 weeks, despite deposition of human CRP and mouse complement component 3 in the plaques. Although female apoE knockouts develop atherosclerosis more rapidly than males, the human CRP transgene is under sex hormone control and is expressed at human levels only in males. We therefore studied only male mice. The concentration of mouse serum amyloid P component, an extremely sensitive systemic marker of inflammation, remained normal throughout except for transient spikes in response to fighting in a few animals, indicating that atherogenesis in this model is not associated with an acute-phase response. However, among human CRP transgenic mice, the circulating CRP concentration was higher in apoE knockouts than in wild-type controls. The higher CRP values were associated with substantially lower estradiol concentrations in the apoE-deficient animals. Human CRP transgene expression is thus up-regulated in apoE-deficient mice, apparently reflecting altered estrogen levels, despite the absence of other systemic signs of inflammation. Extrapolation to human pathology from this xenogeneic combination of human CRP with apoE deficiency-mediated mouse atherosclerosis must be guarded. Nevertheless, the present results do not suggest that human CRP is either proatherogenic or atheroprotective in vivo.atherosclerosis ͉ inflammation ͉ transgenic

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“…C6-deficient rabbits seemed to be protected from lesion development, 19 whereas aortic root lesion size in C5-deficient ApoE-null mice was not different from control ApoE mice. 20 The latter mouse study did not examine more distal regions of the aorta, nor did it examine lesion phenotype. We also did not see statistically significant differences in lipid-positive area of proximal aortic cross sections in complement-deficient and control mice, but we did see differences when aortic arch or descending aorta were analyzed.…”

Section: Buono Et Al Complement and Atherosclerosis 3029mentioning

confidence: 99%

“…19 In contrast, a recent study reported that C5 deficiency does not reduce the development of atherosclerotic lesions in apolipoprotein E (ApoE) deficient mice. 20 Because C3 is the central molecule in both classical and alternative pathways, we reasoned that studying the effect of C3 deficiency on atherosclerosis would be a sensitive way of detecting a relationship between the complement system and atherogenesis. Therefore, we compared extent and phenotype of diet-induced atherosclerotic lesions in LDLR-deficient (ldlr Ϫ/Ϫ ) mice with or without C3 deficiency.…”

mentioning

confidence: 99%