Work

Calcification in Vascular Smooth Muscle Cells Is Associated with Elevated GCLm and Impaired Contraction: Insights into Osteogenic Transdifferentiation and Therapeutic Approaches

Year: 2025

Type: article

Abstract: BACKGROUND: Vascular calcification is a strong predictor of cardiovascular morbidity and mortality. Oxidative stress plays a key role in promoting vascular calcification. Glutathione (GSH), as a major cellular antioxidant, is produced in response to oxidative stress and is regulated by the enzyme glutamate-cysteine ligase (GCL). In this study, we examined the role of the GCL modifier subunit (GCLm) in regulating vascular smooth muscle cell (VSMC) calcification. METHODS: Human coronary artery VSMCs were exposed to phosphate-rich media to induce calcification. RESULTS: Calcification led to a decrease in the GSH:GSSG ratio (reduced glutathione to oxidized glutathione), and elevated GCLm expression, coincident with mobilization of osteogenic genes and loss of contractile phenotype. KEGG pathway analysis of human unstable atherosclerotic plaques similarly showed increased GCLm expression and activation of reactive oxygen species (ROS)-related pathways. Notably, forced overexpression of GCLm in murine VSMCs (MOVAS cells) significantly accelerated calcification. These findings implicate GCLm upregulation in promoting VSMC calcification, potentially by disrupting redox homeostasis and driving phenotypic switching. Further mechanistic studies are warranted to evaluate GCLm as a potential therapeutic target in vascular calcification.

Source: Pathophysiology

DOI: 10.3390/pathophysiology32040066