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Therapeutic Effects of Targeted PPAR? Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo.

ABSTRACT: Rationale: Atherosclerotic plaque is a chronic inflammatory disorder involving lipid accumulation within arterial walls. In particular, macrophages mediate plaque progression and rupture. While PPAR? agonist is known to have favorable pleiotropic effects on atherogenesis, its clinical application has been very limited due to undesirable systemic effects. We hypothesized that the specific delivery of a PPAR? agonist to inflamed plaques could reduce plaque burden and inflammation without systemic adverse effects. Methods: Herein, we newly developed a macrophage mannose receptor (MMR)-targeted biocompatible nanocarrier loaded with lobeglitazone (MMR-Lobe), which is able to specifically activate PPAR? pathways within inflamed high-risk plaques, and investigated its anti-atherogenic and anti-inflammatory effects both in in vitro and in vivo experiments. Results: MMR-Lobe had a high affinity to macrophage foam cells, and it could efficiently promote cholesterol efflux via LXR?-, ABCA1, and ABCG1 dependent pathways, 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. Comprehensive analysis of en face aorta by ex vivo imaging and immunostaining well corroborated the in vivo findings. Conclusion: MMR-Lobe was able to activate PPAR? pathways within high-risk plaques and effectively reduce both plaque burden and inflammation. This novel targetable PPAR? activation in macrophages could be a promising therapeutic strategy for high-risk plaques.

SUBMITTER: Choi JY

PROVIDER: S-EPMC5743459 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo.

Choi Jah Yeon JY Ryu Jiheun J Kim Hyun Jung HJ Song Joon Woo JW Jeon Joo Hee JH Lee Dae-Hee DH Oh Dong Joo DJ Gweon Dae-Gab DG Oh Wang-Yuhl WY Yoo Hongki H Park Kyeongsoon K Kim Jin Won JW

Theranostics 20180101 1

<b>Rationale:</b> Atherosclerotic plaque is a chronic inflammatory disorder involving lipid accumulation within arterial walls. In particular, macrophages mediate plaque progression and rupture. While PPARγ agonist is known to have favorable pleiotropic effects on atherogenesis, its clinical application has been very limited due to undesirable systemic effects. We hypothesized that the specific delivery of a PPARγ agonist to inflamed plaques could reduce plaque burden and inflammation without sy ...[more]

PMID: 29290792

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Project description:ObjectiveVulnerable plaques with fibrous cap thickness (FCT) of ≤65 μm are prone to rupture and/or thrombosis. However, plaques with FCT > 65 μm cause acute myocardial infarction and even sudden death. We aimed to investigate the relationship between 65 < FCT ≤ 80 μm and plaque rupture and/or thrombosis using optical coherence tomography (OCT).MethodsOCT was performed on culprit lesions in 502 consecutively enrolled patients to identify FCT. Patients were classified into three groups according to FCT: Group A (FCT ≤ 65 μm, n = 147), Group B (65 < FCT ≤ 80 μm, n = 84) and Group C (FCT > 80 μm, n = 271). Clinical and laboratory data was collected from the inpatient medical record system.ResultsPlaques with thinner FCT, especially < 65 μm, were more susceptible to rupture and/or thrombosis (P < 0.001). Plaques with FCT between 65 and 80 μm had a higher probability of rupture and/or thrombosis than those with FCT > 80 μm (P < 0.001). In multivariable analysis, FCT ≤ 65 μm and 65 < FCT ≤ 80 μm were independent predictors for plaque rupture ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 8.082, 95% CI = 4.861 to 13.435, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 2.463, 95% CI = 1.370 to 4.430, P = 0.003), thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 25.224, 95% CI = 13.768 to 46.212, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 3.675, 95% CI = 2.065 to 6.542, P < 0.001) and plaque rupture with thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 22.593, 95% CI = 11.426 to 44.674, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 4.143, 95% CI = 1.869 to 9.184, P < 0.001).ConclusionsOCT-assessed 65 < FCT ≤ 80 μm was independently associated with increased risk of plaque rupture and/or thrombosis compared with FCT > 80 μm.

Dataset Information

Therapeutic Effects of Targeted PPAR? Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo.

Publications

Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo.

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