Scap Knockdown In Vasular Smooth Musle Cells Alleviates Atherosclerosis Plaque Formation Via Upregulating Autophagy In ApoE^-/-Mice

Objective: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 determine the mechanism through which SCAP signalling affects VSMC foam cell development.Methods and Results:VSMC-specific SCAP knockdown mice were generated by Cre/LoxP-mediated gene targeting in ApoE-/-mice.Breeding SCAPflox/flox mice with SM22?-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 SM22?-Cre:SCAPflox/+:ApoE^-/-mice fed a Western diet for 12 weeks had significantly fewer atherosclerotic plaques in their aortas than the control mice.Furthermore,we found that autophagy in VSMCs was increased in SM22?-Cre:SCAPflox/+:ApoE^-/-mice.Similarly,invitro,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.Conclusions:VSMC-specific SCAP knockdown decreased lipid accumulation,reduced oxidative stress and prevented AMPK activity damage.These actions alleviated atherosclerosis development via increasing autophagy and excessive lipid deposit clearance in VSMCs.