Student and Faculty Publications
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
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Internal Medicine Commons