HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress

Abstract

Abstract Aims: Phenotypic change of vascular smooth muscle cells (VSMCs) contributes a lot in obesity induced vascular pathological remodeling. The endoplasmic reticulum (ER) is critical for maintaining VSMC function, but the accumulation of misfolded proteins in the ER impairs cell function. As the major ER protein quality control responsible for clearing misfolded proteins, ER-associated degradation (ERAD) whose key member is HRD1 plays vital role in lipid metabolism, but its function in VSMC phenotypic change remains poorly understood. Main methods: The level of HRD1 expression was analyzed in aortic tissues of mice fed with a high-fat diet (HFD). The HE and EVG (VERHOEFF’S VAN GIESON) staining were used to demonstrate vascular pathological changes. Cripr and transcriptomic analysis were applied in in vitro studies to explore the cellular mechanism. Key findings: Data showed a significant reduction of HRD1 in aortic tissues of mice under HFD feeding. VSMC phenotypic change and HRD1 downregulation were detected by cholesterol treatment. Transcriptomic and further analysis of HRD1-KO VSMCs showed that HRD1 deficiency increased the expression of genes related with ER stress, proliferation, and migration, but decreased the VSMC contractile-related genes. HRD1 deficiency in VSMCs also exacerbated the proliferation, migration, and ROS production induced by cholesterol, which promoted the VSMC phenotypic change process. Significance: Our results proved that HRD1 plays an essential role in the contractile homeostasis of VSMCs by negatively regulating ER stress. Thus, HRD1 may have the potential to be a therapeutic target in lipid metabolic disorders induced vascular remodeling caused by VSMC phenotypic change.