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. 2000 Apr 17;191(8):1437-42.
doi: 10.1084/jem.191.8.1437.

Infectious agents are not necessary for murine atherogenesis

S D Wright  1 , C Burton, M Hernandez, H Hassing, J Montenegro, S Mundt, S Patel, D J Card, A Hermanowski-Vosatka, J D Bergstrom, C P Sparrow, P A Detmers, Y S Chao
Affiliations

Infectious agents are not necessary for murine atherogenesis

S D Wright et al. J Exp Med. .

Abstract

Recent work has revealed correlations between bacterial or viral infections and atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been observed at high frequency in human atherosclerotic lesions, prompting the hypothesis that infectious agents may be necessary for the initiation or progression of atherosclerosis. To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E(-/)- (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals. We further tested the role of infectious agents by creating a colony of germ-free apo E(-/)- mice. These animals are free of all microbial agents (bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge. These studies show that infection is not necessary for murine atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be fulfilled for any infectious agent in atherosclerosis.

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Figures

Figure 1
Figure 1
Accumulation of cholesterol ester in the aortas of apo E−/− and apo E−/−/lpsdmice fed a high-fat diet. Animals were weaned onto a high-fat diet, and at the indicated times, aortic cholesterol measurements were performed as described in Materials and Methods. Each data point represents the average value from 7–10 animals, with error bars indicating the SE.
Figure 2
Figure 2
Plasma lipid profiles and aortic cholesterol levels of germ-free (white bars) and control (black bars) apo E−/− mice. Apo E−/− mice were reared germ free or in the presence of ambient pathogens. At 22 or 32 wk of age, animals were killed, blood was collected for analysis of plasma cholesterol and triglyceride, and aortas were harvested and extracted for determination of cholesterol content. (A and B) Comparisons of plasma cholesterol and triglyceride levels in control and germ free yield nearly identical values in male (A) and female (B) apo E−/− mice at both 22 and 32 wk. None of the small differences reached statistical significance, with the exception of decreased triglyceride levels for the male germ-free animals at 22 wk (*P < 0.005) and increased triglyceride levels for the female germ-free animals at 32 wk (**P = 0.03). (C and D) Comparisons of aortic free cholesterol and cholesteryl ester levels in male (C) and female (D) apo E−/− mice at 22 and 32 wk show a trend toward lower levels in the germ-free animals at both time points, although statistical significance was achieved only for the cholesteryl ester in germ-free males at 22 wk (*P < 0.005) and for the germ-free cholesterol in germ-free females at 22 wk († P = 0.05). However, data shown are expressed on a per aorta basis, and after correction for the decreased body weight of the germ-free mice, none of the differences attained statistical significance. For each time point and sex, group size was ≥10 animals, with the exception of the 32-wk male germ-free mice, which were reduced to 3 by mortality caused by aggressive behavior.
Figure 3
Figure 3
Histology of aortic root lesions in germ-free and control apo E−/− mice. (A and B) Cryosections of the aortic root area in mice at 22 wk of age were stained with hematoxylin-phyloxine-saffron. Lesions in both types of animal have fibrous components (indicated by yellow staining) and large areas that are rich in foam cells (indicated by light purple staining). White rice grain–shaped spaces indicative of the extracellular deposition of cholesterol are also visible in lesions from control and germ-free mice. The tissue staining red is surrounding muscle. Bar = 156 μm. (C and D) These sections are stained brown for the T lymphocyte marker CD4. Arrowheads indicate the location of T lymphocytes, present in both control and germ-free animals. Bar = 31 μm. Hearts from five mice of each type for both males and females were examined histologically, and the sections shown are representative of the results from all of the mice. The same morphology and cellular composition was observed in both female and male mice. Histology of hearts from two mice of each type at 32 wk of age similarly revealed no differences between germ-free apo E−/− and control apo E−/− mice (not shown). Additionally, staining for the macrophage marker CD11b revealed comparably stained areas in control and germ-free animals (not shown).
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