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SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE(-/-) mice

Li, D; Chen, A; Lan, T; Zou, Y; Zhao, L; Yang, P; Qu, H; ... Ruan, XZ; + view all (2019) SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE(-/-) mice. FASEB Journal , 33 (3) pp. 3437-3450. 10.1096/fj.201800975RRR.

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Abstract

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that plays a critical role in regulating intracellular cholesterol levels, but the association between SCAP and foam cell formation in vascular smooth muscle cells (VSMCs) is poorly understood. Using tissue-specific SCAP knockdown in ApoE-/- mice, we sought to search the mechanism through which SCAP signalling affects VSMC foam cell development. VSMC-specific SCAP knockdown mice were generated by Cre/LoxP-mediated gene targeting in ApoE-/- mice. Breeding SCAPflox/flox mice with SM22α-Cre mice resulted in no viable offspring with the homozygote SM22-Cre: SCAPflox/flox genotype due to embryonic lethality. Interestingly, we found that the heterozygote SM22α-Cre:SCAPflox/+:ApoE-/- mice fed a Western diet for 12 weeks had significantly fewer atherosclerotic plaques in their aortas than the control mice due to reduced cholesterol uptake and synthesis. Furthermore, we found that autophagy in VSMCs was increased in SM22α-Cre:SCAPflox/+:ApoE-/- mice. Similarly, in vitro, SCAP knockdown in human coronary artery VSMCs by RNA interference reduced lipid accumulation and increased autophagy under low-density lipoprotein (LDL) cholesterol loading. SCAP knockdown in VSMCs reduced oxidative stress and increased AMPK phosphorylation, which contributed to the upregulation of autophagy in vivo and in vitro. VSMC-specific SCAP knockdown decreased the lipid accumulation and intracellular oxidative stress and interestingly increased excessive lipid clearance by enhancing lipid autophagy mediated by ROS/AMPK pathway in VSMCs, consequently alleviated atherosclerosis plaque formation.

Type: Article
Title: SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE(-/-) mice
DOI: 10.1096/fj.201800975RRR
Publisher version: https://doi.org/10.1096/fj.201800975RRR
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Atherosclerosis, SCAP, Autophagy, AMPK pathway
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10071584
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