Dataset Information

Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

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 ?/? (PPAR?/?). Overall, our data demonstrate that lanatoside C aggravates the development of atherosclerosis by inducing PPAR?/? expression, which mediates upregulation of SR-A and CD36, and promotes oxLDL uptake and foam-cell formation.

SUBMITTER: Shi H

PROVIDER: S-EPMC4731744 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

Shi Huairui H Mao Xiaobo X Zhong Yucheng Y Liu Yuzhou Y Zhao Xiaoqi X Yu Kunwu K Zhu Ruirui R Wei Yuzhen Y Zhu Jianghao J Sun Haitao H Mao Yi Y Zeng Qiutang Q

Scientific reports 20160129

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 dev ...[more]

PMID: 26821916

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Project description:Vascular smooth muscle cells (VSMCs) are an important source of foam cells in atherosclerosis. The mechanism for VSMC-derived foam cell formation is, however, poorly understood. Here, we demonstrate that the P2RY12/P2Y12 receptor is important in regulating macroautophagy/autophagy and VSMC-derived foam cell formation in advanced atherosclerosis. Inhibition of the P2RY12 receptor ameliorated lipid accumulation and VSMC-derived foam cell formation in high-fat diet-fed apoe-/- mice (atherosclerosis model) independent of LDL-c levels. Activation of the P2RY12 receptor blocked cholesterol efflux via PI3K-AKT, while genetic knockdown or pharmacological inhibition of the P2RY12 receptor inhibited this effect in VSMCs. Phosphoproteomic analysis showed that the P2RY12 receptor regulated the autophagy pathway in VSMCs. Additionally, activation of the P2RY12 receptor inhibited MAP1LC3/LC3 maturation, SQSTM1 degradation, and autophagosome formation in VSMCs. Genetic knockdown of the essential autophagy gene Atg5 significantly attenuated P2RY12 receptor inhibitor-induced cholesterol efflux in VSMCs. Furthermore, activation of the P2RY12 receptor led to the activation of MTOR through PI3K-AKT in VSMCs, whereas blocking MTOR activity (rapamycin) or reducing MTOR expression reversed the inhibition of cholesterol efflux mediated by the P2RY12 receptor in VSMCs. In vivo, inhibition of the P2RY12 receptor promoted autophagy of VSMCs through PI3K-AKT-MTOR in advanced atherosclerosis in apoe-/- mice, which could be impeded by an autophagy inhibitor (chloroquine). Therefore, we conclude that activation of the P2RY12 receptor decreases cholesterol efflux and promotes VSMC-derived foam cell formation by blocking autophagy in advanced atherosclerosis. Our study thus suggests that the P2RY12 receptor is a therapeutic target for treating atherosclerosis.Abbreviations: 2-MeSAMP: 2-methylthioadenosine 5'-monophosphate; 8-CPT-cAMP: 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic-monophosphate; ABCA1: ATP binding cassette subfamily A member 1; ABCG1: ATP binding cassette subfamily G member 1; ACTB: actin beta; ADPβs: adenosine 5'-(alpha, beta-methylene) diphosphate; ALs: autolysosomes; AMPK: AMP-activated protein kinase; APOA1: apolipoprotein A1; APs: autophagosomes; ATG5: autophagy related 5; ATV: atorvastatin; AVs: autophagic vacuoles; CD: chow diet; CDL: clopidogrel; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; dbcAMP: dibutyryl-cAMP; DIL-oxLDL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine-oxLDL; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; EVG: elastic van gieson; HE: hematoxylin-eosin; HDL: high-density lipoprotein; HFD: high-fat diet; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDL-c: low-density lipoprotein cholesterol; LDs: lipid droplets; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Masson: masson trichrome; MCPT: maximal carotid plaque thickness; MK2206: MK-2206 2HCL; NBD-cholesterol: 22-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl] amino)-23,24-bisnor-5-cholen-3β-ol; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; ORO: oil Red O; ox-LDL: oxidized low-density lipoprotein; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TIC: ticagrelor; ULK1: unc-51 like autophagy activating kinase 1; VSMCs: vascular smooth muscle cells.

Dataset Information

Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

Publications

Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

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