Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

Huairui Shi,Yi Mao,Qiutang Zeng,Yuzhou Liu,Ruirui Zhu,Xiaoqi Zhao,Kunwu Yu,Yucheng Zhong,Yuzhen Wei,Jianghao Zhu,Haitao Sun,Xiaobo Mao

doi:10.1038/srep20154

Huairui Shi, Yi Mao + Show 10 more

Open Access

https://doi.org/10.1038/srep20154

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Abstract

Lanatoside C’s impact on atherosclerosis is poorly understood. The present study was conducted to determine whether lanatoside C affects the development of atherosclerosis in apolipoprotein E-deficient (ApoE–/–) mice. ApoE–/– mice were administered either phosphate-buffered saline (PBS) containing 0.1% DMSO (the vehicle control group) or lanatoside C at low (1 mg/kg per day) or high (2 mg/kg per day) doses, and fed a Western diet for 12 weeks. Lanatoside C dose-dependently aggravated the development of atherosclerosis in the ApoE–/– mice compared with the vehicle control group. In an effort to determine the mechanism by which lanatoside C increased atherosclerosis, we found that lanatoside C significantly promoted the uptake of oxidised low-density lipoprotein (oxLDL) and increased foam-cell formation by upregulation of scavenger receptor class A (SR-A) and the class B scavenger receptor (CD36) in macrophages. Meanwhile, the effects of lanatoside C were abolished using small interfering RNA (siRNA) inhibition of peroxisome proliferator-activated receptors β/δ (PPARβ/δ). Overall, our data demonstrate that lanatoside C aggravates the development of atherosclerosis by inducing PPARβ/δ expression, which mediates upregulation of SR-A and CD36, and promotes oxLDL uptake and foam-cell formation.

Highlights

Atherosclerosis is a chronic disease of the large arteries that is an important cause of morbidity and mortality in industrialised nations[1,2]
To investigate the potential effects of lanatoside C on atherosclerosis, we evaluated the severity of atherosclerosis based on the morphological and histological changes that occurred in mice treated with approximately 20 μ g of lanatoside C or 40 μ g of lanatoside C, compared to the vehicle control (PBS containing 0.1% DMSO)
Atherosclerosis is an inflammatory response of macrophages and lymphocytes to invading pathogenic lipoproteins in the arterial wall, and formation of foam cells by macrophages in the intima is a major hallmark of early-stage atherosclerotic lesions[37,38,39]

Summary

Introduction

Atherosclerosis is a chronic disease of the large arteries that is an important cause of morbidity and mortality in industrialised nations[1,2]. The role of foam cells as the major culprit in atherosclerosis has been further demonstrated by the resistance to atherosclerosis in ApoE–/– mice[5,6] This unrestricted uptake through scavenger receptor pathways, which is not limited by intracellular cholesterol levels, eventually leads to the formation of foam cells, the initial step in atherosclerosis[7,8]. Macrophage scavenger receptor class A (SR-A) and CD36, a member of the type B family, are thought to play significant roles in foam-cell formation because of their ability to promote uptake-modified lipids, such as oxLDL7,10. ATP-binding cassette (ABC) transporters (ABCA1 and ABCG1) and SR-BI, another type B scavenger receptor, protect against foam-cell formation when expressed in macrophages, by stimulating cholesterol efflux[17,18,19]. The present study was conducted to determine whether the cardiac glycoside lanatoside C affects the development of atherosclerosis in ApoE–/– mice

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