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.
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
Transgenic mice overexpressing the human dysfunctional apolipoprotein E variant, APOE*3 Leiden, develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. In the present study, we investigated the effects of diet composition and feeding period on serum cholesterol exposure and the amount of atherosclerosis in the aortic sinus in these mice, using quantitative image analysis. On each of the three diets tested--a low-fat diet, a high-saturated-fat/cholesterol diet, and a high saturated-fat/high-cholesterol/0.5%-cholate diet--transgenic animals showed a marked hyperlipidemia compared with nontransgenic littermates. Measurement of the atherosclerotic lesion areas in cross sections of the aortic sinus in animals exposed to these three diets for up to 6 months showed a 5 to 10 times greater lesion area in transgenic mice compared with nontransgenic controls. Highly significant positive correlations were found between the log-transformed data on lesion area and serum cholesterol exposure (r = .82 to .85 for the 1-, 2-, and 3-month treatment groups), indicating that the hyperlipidemia is likely to be a major determinant in lesion formation. On the basis of these findings, we suggest that the APOE*3 Leiden mouse represents a promising model for intervention studies with hypolipidemic and antiatherosclerotic drugs.
A number of agents that mimic the ability of the thyroid hormone, T3, to decrease plasma cholesterol levels are described; one is as effective as T3 at reducing cholesterol levels and stimulating liver function, but has very little effect on cardiac function and is thus less likely to be toxic. The agent may be useful in the treatment of atherosclerosis.
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