UNDERSTANDING THE ROLE OF SESTRIN2 IN ANGIOGENESIS AND RISK OF ISCHEMIC DISEASES ASSOCIATED WITH DIABETES: AN IN-VITRO STUDY AND HUMAN INVESTIGATION IN PARTICIPANTS OF QATAR BIOBANK

Abstract

Diabetes mellitus and cardiovascular disease represent converging global epidemics, primarily driven by diabetes-induced endothelial dysfunction and impaired reparative angiogenesis. The stress-inducible protein Sestrin2 (SESN2) has been identified as a potential guardian of vascular health, but its precise role and clinical significance in the diabetic milieu remain poorly defined. This dissertation tested the central hypothesis that SESN2 is a critical regulator of endothelial angiogenesis and that its dysregulation is a key contributor to diabetic vascular complications, employing a multi-scale approach from molecular dynamics to population health. In-vitro, using human endothelial cells under glycative stress, this work established that SESN2 is indispensable for angiogenic potential. SESN2 overexpression preserved cell proliferation, invasion, and tube formation by activating the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) antioxidant axis, upregulating vascular endothelial growth factor (VEGF), and maintaining pro-survival AKT signaling while preventing mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) hyperactivation. Conversely, silencing SESN2 exacerbated stress-induced apoptosis, an outcome supported by transcriptomic analyses that showed SESN2 loss suppresses angiogenic gene networks while promoting apoptotic pathways. A study of the Qatar Biobank cohort revealed a critical clinical paradox. Higher circulating SESN2 was protective in healthy individuals but was associated with a greater cardiometabolic burden in patients with type 2 diabetes. This suggests SESN2's role shifts from a marker of resilience to a distress signal of overwhelming cellular stress. This finding was corroborated by deep learning-based retinal analysis, where high SESN2 expression correlated with increased vascular density and systemic VEGF levels. At the atomic level, computational modeling elucidated the mechanism of SESN2 as a specific leucine sensor, uncovering a novel allosteric compaction mechanism essential for its function. This structural insight enabled the successful virtual screening and identification of novel, potent small-molecule binders. In conclusion, this dissertation establishes SESN2 as a critical, context-dependent regulator of vascular homeostasis. Its role transitions from a protective guardian in health to a biomarker of severe metabolic distress in chronic diabetes. These findings resolve a key clinical paradox and position SESN2 as a promising target for both diagnostic and therapeutic interventions in diabetic vascular complications.