THE MOLECULAR MECHANISMS UNDERPINNING THE ROLE OF SESTRIN 2 IN ENDOTHELIAL FUNCTION

Abstract

Cardiovascular diseases (CVD) associated with diabetes persist to be a major cause of death worldwide. Endothelial dysfunction (ED), a condition characterized by impaired Nitric Oxide (NO) bioavailability in endothelial cells, is a hallmark of diabetes and is the initial step in the development of cardiovascular disturbances. A major molecular contributor to the pathogenesis of diabetes and onset of endothelial dysfunction is oxidative stress, a condition resulting from excessive reactive oxygen species (ROS) production and concurrent reduction in antioxidant capacity. Heightened oxidative stress, is crucial in the etiology of CVD, especially in individuals with diabetes. Sestrin 2, one of the first responders to oxidative stress, has been the focus of several studies that highlighted its cardioprotective role. However, its exact role in endothelial dysfunction associated with diabetes is not fully elucidated. This thesis examines the molecular mechanisms behind Sestrin 2's function in endothelial function and its potential as a biomarker for ED and cardiovascular complications related to diabetes. The study utilized both in vitro and human studies to clarify Sestrin 2's s protective benefits against methylglyoxal (MGO)-induced endothelium injury, a consequence of hyperglycemia. Microarray profiling, miRNA expression analysis, and pathway enrichment analyses indicated that SESN2 modulates critical pathways associated with oxidative stress, inflammation, and endothelial-to-mesenchymal transition (EndMT). Moreover, SESN2 deficiency aggravated MGO-induced reactive oxygen species (ROS) generation, reduced endothelial nitric oxide synthase (eNOS) functionality, and enhanced pro-inflammatory cytokine expression. In a human cohort from Qatar Biobank, circulating Sestrin 2 levels were negatively correlated with indicators of glycemic control, insulin resistance, and lipid profiles, indicating its potential as a predictive biomarker for CVD risk assessment in diabetic patients. These findings emphasize Sestrin 2's essential function in preserving endothelial integrity and indicate its therapeutic potential in mitigating diabetes-related vascular complications. By deciphering the molecular links between Sestrin 2 and eNOS regulation, this work provides novel insights into the development of targeted therapies aimed at restoring endothelial function and reducing CVD burden. Moreover, this work evaluates the value of Sestrin 2 as a prognostic biomarker for cardiovascular disturbances associated with diabetes.