Abstract 445: Increasing Macrophage Survival Delays Progression of Advanced Atherosclerotic Lesions Through Macrophage-Derived ApoE

Abstract

Introduction/Hypothesis: We previously demonstrated that increasing macrophage survival delayed atherosclerotic plaque progression towards advanced stages. However, whether cell death-protected macrophages would still be efficient to hinder the progression and favor the resolution of already advanced atherosclerotic lesions, and thus prove therapeutic potential, remains unknown. Methods: We used a transgenic mouse model in which macrophage lifespan is enhanced through specific overexpression of the antiapoptotic gene hBcl-2 under the control of the macrophage specific CD68 promoter (Mø-hBcl2). Apoe -/- or Ldlr -/- recipient mice with advanced atherosclerotic lesions were irradiated and then transplanted with bone marrow cells isolated from Apo e -/- Mø-h Bcl2 or Apo e +/+ Mø-hBcl2 mice respectively and their appropriate controls. Results: Both Apoe -/- Mø-h Bcl2 → Apoe -/- and Apoe +/+ Mø-h Bcl2 → Ldl r -/- mice presented a significant decrease in lesional apoptotic cells content (-30%, P<0.05) as compared to their respective controls. Additionally, hBcl2 expression in macrophages was associated with a larger pool of tissue macrophages in vivo, including Küppfer cells in the liver, in both Apoe -/- (+40% P<0.05) and Ldlr -/- (+36% P<0.05) recipients. By contrast, only Ldlr -/- recipient mice showed reduction of lesional necrotic areas (-37%, P<0.05), plasma cholesterol levels (-15%, P<0.05) and atherosclerotic lesions (-30%, P<0.05). As those reductions were not significant in the context of ApoE deficiency, these findings supported that Mø-derived ApoE was key in regulating plasma cholesterol levels, lesional necrosis and advanced plaque progression in the context of increased macrophage pool. Indeed, increased liver Küpffer cells content in the liver of Ldlr -/- recipient mice was associated with elevated ApoE mRNA levels (+30%, P<0.05), which is likely to promote reverse cholesterol transport. Conclusions: Collectively, these data suggest that macrophage survival hindered advanced lesion progression. One potential mechanistic explanation lied to the increased Küpffer cells content, which could modulate directly or indirectly cholesterol homeostasis.