Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation

Authors

Abhijnan Chattopadhyay
Pujun Guan
Suravi Majumder
Kaveeta Kaw
Zhen Zhou
Chen Zhang
Siddharth K Prakash
Anita Kaw
L Maximillian Buja
Callie S Kwartler
Dianna M Milewicz

Publication Date

8-1-2022

Journal

Arteriosclerosis, Thrombosis, and Vascular Biology

Abstract

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when

CONCLUSIONS: Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.

Keywords

Animals, Atherosclerosis, Cells, Cultured, Cholesterol, Endoplasmic Reticulum, Male, Mice, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Plaque, Atherosclerotic, eIF-2 Kinase