MECHANISMS BY WHICH CMV MAY CONTRIBUTE TO ATHEROGENESIS AND RESTENOSIS

越来越多的证据表明人类

Increasing evidence suggests human cytomegalovirus (HCMV) infection contributes to the development of atherosclerosis. We investigated the relationship between cytomegalovirus and atherosclerosis by inoculating mice with cytomegalovirus (CMV) or virus free media. Since mice are generally resistant to the development of atherosclerosis, we used C57BL/6J apolipoprotein-e knockout mice which have been genetically engineered to develop premature atherosclerosis. Sixty mice (f=28, m=32)thirteen to fourteen days old received an intraperitoneal injection of either murine CMV (30,000 PFU)(n=30) or virus free media (n=30). Murine CMV was cultured in embryonic mouse fibroblasts. Virus free media was prepared by filtering the virus with a 0.1 um filter. All animals were kept in a sterile environment and given a regular chow diet. Half the animals were sacrificed at 13 weeks of age and the other half at sixteen weeks of age (n=15/group) since the ideal time to assess for a difference in atherosclerosis was unknown. The natural progression begins at ten weeks with fatty plaques and continues to progress to its final fibrous plaque at twenty weeks on a regular chow diet. Atherosclerosis was assessed for each mouse by examining the aortic sinus (an area at the level of the heart valves known to be predisposed to atherosclerosis in mice). An outside histologist who was blinded stained the tissues for fat and calculated the lipid surface area per cross-section. In all groups there was a trend that CMV infected mice had more atherosclerosis and the difference was greatest in older mice. At thirteen weeks of age the difference between the mean lesion area in the CMV infected group was only 9% and at sixteen weeks of age the difference was 30% (P=0.01). Subgroup analysis revealed a significant difference (P=0.04) between the female groups [mCMV=119+/-17(um x10+/-SEM;n=sections)vs. control=98+/-14] and no significant difference (P=0.09) between the male groups (54+/-8 vs. 47+/-7). Serum samples were obtained immediately prior to sacrifice and data is currently available for the sixteen-week-old animals. CRP levels (mean mg/L+/-SEM;n=4/group) in these mCMV mice (14+/-4) were higher than the control (10+/-4) but the difference was not significant. The mCMV infected mice (n=3) had the following plasma lipid levels (mean mg/dL+/-SEM); TC=638+/-86, TTG=105+/-21, HDL=23+/-4 and the control mice (n=3) had TC=632+/-114, TTG=114+/-25, and HDL=22+/-5. The CMV group had lower Gamma-IF (mean pg/mL+/-SEM;677+/-396 vs. 1024+/-579;n=4/group) and higher IL-4(mean pg/ml+/-SEM;98+/-29 vs 76+/-29) although no difference was significant. In summary, mCMV significantly increased the development of atherosclerosis in C57BL/6J apoE -/- congenic mice and the difference was greatest in sixteen-week-old females. Cytokine analysis suggests that this difference is due to a Th-2 response.