Glutathione as a Therapeutic Agent for OxLDL-Induced Endothelial Dysfunction and Atherosclerosis Prevention.

Abstract

Endothelial dysfunction is a critical contributor to atherosclerosis and cardiovascular diseases, driven by oxidative stress and inflammation induced by oxidized low-density lipoprotein (oxLDL). This study investigates the protective effects of reduced glutathione (GSH) against oxLDL-induced endothelial dysfunction using human umbilical vein endothelial cells (HUVECs) as an in vitro model. Our findings demonstrate that oxLDL exposure significantly reduces cell viability, induces oxidative stress, and promotes endothelial injury by upregulating LOX-1 expression, decreasing nitric oxide (NO) production, and impairing endothelial nitric oxide synthase (eNOS) activity. Pretreatment with GSH effectively restores cell viability, reduces ROS generation, suppresses LOX-1 expression, and preserves NO bioavailability by maintaining eNOS activity. Additionally, GSH enhances the antioxidant defense system by increasing superoxide dismutase, catalase, and glutathione peroxidase levels while reducing lipid peroxidation, as indicated by lower malondialdehyde content. Beyond its antioxidative properties, GSH exhibits antiapoptotic effects by restoring the Bax/Bcl-2 balance, inhibiting cytochrome C release, and suppressing caspase-3 activation, thereby preventing mitochondrial membrane depolarization. Furthermore, GSH mitigates endothelial inflammation by downregulating intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. These findings highlight GSH's potential as a therapeutic agent for protecting endothelial cells against oxLDL-induced dysfunction by alleviating oxidative stress, apoptosis, and inflammation, ultimately contributing to the prevention of atherosclerosis progression.