Abstract 17987: Therapeutic Effects of Targeted PPARγ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging in vivo

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Abstract

Background: Atherosclerotic plaque is a chronic inflammatory disorder with lipid accumulation within arterial walls. In particular, macrophages mediated plaque progression and rupture. While PPARγ agonist is known to have favorable pleiotropic effects on atherogenesis, its clinical application has been limited due to undesirable systemic effects.

Hypothesis: We hypothesized that macrophage mannose receptor (MMR)-targeted nanocarrier loaded with lobeglitazone could 1) activates PPARγ pathway within plaque specifically and 2) reduce plaque burden and inflammation.

Method and Results: We newly developed macrophage mannose receptor (MMR)-targeted biocompatible nanocarrier loaded with lobeglitazone (MMR-Lobe), which is able to specifically activate PPARγ pathways within the inflamed high-risk plaques. MMR-Lobe had a high affinity to macrophage foam cells, and it could efficiently promote cholesterol efflux via LXRα-, ABCA1, ABCG1 dependent pathway, and inhibit plaque protease expression. Using in vivo serial optical imaging of carotid artery, MMR-Lobe markedly reduced both plaque burden and inflammation in atherogenic mice without undesirable systemic effects (Figure). Immunofluorescence analysis from the plaque, co-activation of PPARγ, LXRα, ABCA1, and ABCG1 were strongly enhanced by MMR-Lobe treatment, whereas the expression of MMP-9 decreased significantly in the MMR-Lobe mice as compared to those in lobeglitazone per se group or controls. Comprehensive analysis of en face aorta by ex vivo imaging and immunostainings well corroborated the in vivo findings.

Conclusion: This novel targetable PPARγ activation in macrophages could be a promising therapeutic strategy for high-risk plaques.

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