LMO7 regulates smooth muscle cell cholesterol esterification to influence plaque stability

Abstract Smooth muscle cells (SMC) can undergo distinct fate transitions that influence atherosclerotic plaque phenotype: SMC make up the protective fibrous cap that prevents plaque rupture, but can also transdifferentiate to a destabilizing pro-inflammatory phenotype. We found that LMO7, a scaffolding protein that modulates SMC phenotype, is induced in atherosclerosis. SMC LMO7 deletion produced a paradoxical phenotype with enhanced indices of plaque stability despite greater lipid content. We determined that LMO7 promotes SOAT1 ubiquitination and degradation. LMO7 depletion thus favored cholesterol esterification and “safe” storage, relieving ER stress and subsequent induction of KLF4 and SMC transdifferentiation. Immunostaining and single cell sequencing confirmed that SMC LMO7 depletion enhanced cap stabilizing fate transitions while substantially reducing inflammatory transdifferentiation. Similarly, LMO7 was induced in human atherosclerosis, but at lower levels in stable versus ruptured plaques. These findings reveal that SMC cholesterol esterification, rather than total cholesterol content, influences plaque composition and stability.