The role of a murine transplantation model of atherosclerosis regression in drug discovery - PubMed (original) (raw)

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The role of a murine transplantation model of atherosclerosis regression in drug discovery

Jonathan E Feig et al. Curr Opin Investig Drugs. 2009 Mar.

Abstract

Atherosclerosis is the leading cause of death worldwide. To date, the use of statins to lower LDL levels has been the major intervention used to delay or halt disease progression. These drugs have an incomplete impact on plaque burden and risk, however, as evidenced by the substantial rates of myocardial infarctions that occur in large-scale clinical trials of statins. Thus, it is hoped that by understanding the factors that lead to plaque regression, better approaches to treating atherosclerosis may be developed. A transplantation-based mouse model of atherosclerosis regression has been developed by allowing plaques to form in a model of human atherosclerosis, the apoE-deficient mouse, and then placing these plaques into recipient mice with a normolipidemic plasma environment. Under these conditions, the depletion of foam cells occurs. Interestingly, the disappearance of foam cells was primarily due to migration in a CCR7-dependent manner to regional and systemic lymph nodes after 3 days in the normolipidemic (regression) environment. Further studies using this transplant model demonstrated that liver X receptor and HDL are other factors likely to be involved in plaque regression. In conclusion, through the use of this transplant model, the process of uncovering the pathways regulating atherosclerosis regression has begun, which will ultimately lead to the identification of new therapeutic targets.

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Figure 1

Figure 1. Regression of advanced atherosclerotic plaques in the mouse transplantation model

Mice null for apolipoprotein E were fed a Western diet for 40 weeks to promote advanced atherosclerosis. Aortic arches from these mice were either harvested and analyzed by (A) histochemical and (B) histomorphometric methods, or were transplanted into apolipoprotein E-null ('progression') or wild-type ('regression') recipient mice. After 9 weeks, the same analyses were conducted on the aortic arches from transplantation recipients. The histochemical results for the foam cell marker CD68 (brown) and the vascular smooth cell marker α-actin (purple) are illustrated. The images demonstrate the immunostaining of representative aortic plaques in cross section. Note the low levels of foam cells and the appearance of a fibrous cap in the regression group. In contrast to the results in the regression mice, the progression group demonstrated a persistence of foam cells and no development of a fibrous cap. As shown in panel B, the visual histochemical staining suggesting a large depletion of foam cells was confirmed by quantitative analysis of the plaque area stained for CD68. NS not significant (Adapted with permission from Lippincott Williams & Wilkins and Trogan E, Fayad ZA, Itskovich VV, Aguinaldo JGS, Mani V, Fallon JT, Chereshnev I, Fisher EA: Serial studies of mouse atherosclerosis by in vivo magnetic resonance imaging detect lesion regression after correction of dyslipidemia. Arterioscler Thromb Vasc Biol (2004) 24(9):1714–1719. © 2004 Lippincott Williams & Wilkins)

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