The regression of atherosclerosis: Molecular insights from novel mouse models

Atherosclerosis is the leading underlying cause of death in the developed world. We have developed a transplantation-based mouse model of atherosclerosis regression by allowing plaques to form in a model of human atherosclerosis, the apoE-deficient (apoE-/-) mouse, and then placing them into a recipient mouse with a normolipidemic plasma environment. In this model, we reported emigration of plaque cells filled with cholesterol (macrophage foam cells) to regional and systemic lymph nodes after three days in the normolipidemic (regression) environment. Experimentation revealed that under regression conditions, emigration required the expression of the chemokine receptor CCR7 on the macrophage foam cells. Importantly, we discovered that both LXRalpha and LXRbeta, nuclear hormone receptors that play key roles in maintaining cholesterol homeostasis in macrophages, are required for maximal CCR7 gene expression and macrophage foam cell depletion and migration out of plaques in vivo. Given the strong inverse correlation between plasma HDL and the risk of cardiovascular disease, we next wondered whether HDL was a regression factor. Interestingly, we found that the restoration in apoE-/- mice of a naturally low plasma HDL to normal levels, despite persistent hyperlipidemia, can promote macrophage foam cell depletion and migration. Surprisingly, deficiency of HDL, despite normolipidemia, impaired macrophage foam cell depletion and migration. Furthermore, the HDL deficiency was associated with diminished CCR7 expression in macrophage foam cells and decreased expression of markers of the M2 (anti-inflammatory) macrophage state, whereas the opposite pattern was seen in mice with the restored HDL levels. In order to assess whether any of our observations was reflective of the regression process itself, and not model specific, we studied a non-transplant mouse model of regression (the "Reversa" mouse) and found that indeed key features of regression- the induction of CCR7 expression in macrophage foam cells, the migration of these cells out of the plaque, and their skewing towards the M2-like state- were also observed in this model. Further study at the molecular level is hoped to lead to the identification of critical pathways that can be manipulated to develop new therapies to promote the regression of atherosclerosis.