Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial cell dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions.

A timely and adequate response to stress is inherently present in each cell and is important for maintaining the proper functioning of the cell in changing intracellular and extracellular environments. Disruptions in the functioning or coordination of defense mechanisms against cellular stress can reduce the tolerance of cells to stress and lead to the development of various pathologies. Aging also reduces the effectiveness of these defense mechanisms and results in the accumulation of cellular lesions leading to senescence or death of the cells. Endothelial cells and cardiomyocytes are particularly exposed to changing environments. Pathologies related to metabolism and dynamics of caloric intake, hemodynamics, and oxygenation, such as diabetes, hypertension, and atherosclerosis, can overwhelm endothelial cells and cardiomyocytes with cellular stress to produce cardiovascular disease. The ability to cope with stress depends on the expression of endogenous stress-inducible molecules. Sestrin2 (SESN2) is an evolutionary conserved stress-inducible cytoprotective protein whose expression is increased in response to and defend against different types of cellular stress. SESN2 fights back the stress by increasing the supply of antioxidants, temporarily holding the stressful anabolic reactions, and increasing autophagy while maintaining the growth factor and insulin signaling. If the stress and the damage are beyond repair, SESN2 can serve as a safety valve to signal apoptosis. The expression of SESN2 decreases with age and its levels are associated with cardiovascular disease and many age-related pathologies. Maintaining sufficient levels or activity of SESN2 can in principle prevent the cardiovascular system from aging and disease.

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial–mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation.

Diabetes mellitus is prevalent worldwide, with vascular complications responsible for over 70% of deaths associated with the condition. Methylglyoxal (MGO), a by-product of glycolysis, is a significant modulator of vascular dysfunction in diabetes. Sestrin2 (SESN2) has been recognized as a vital regulator of cellular homeostasis and stress responses. Although SESN2’s role in cellular defense is gaining recognition, its precise function in endothelial cells under diabetic-like conditions remains poorly understood. This study examines the role of SESN2 in preserving endothelial cell angiogenic function under MGO-induced stress. The study reveals that SESN2 is a vital regulator of multiple protective pathways, as demonstrated by both loss-of-function and gain-of-function approaches in EA.hy926 endothelial cells. Our data showed that SESN2 overexpression significantly maintained tubular network formation, proliferation, and invasive capacity under MGO stress, whereas SESN2 silencing exacerbated MGO-induced impairment of angiogenic capacity. SESN2 was identified as orchestrating NRF2/HO-1 antioxidant pathway activation while simultaneously enhancing VEGF-C expression, offering a dual strategy for cellular protection and angiogenesis. Moreover, SESN2 facilitated a regulated equilibrium of the AKT/mTOR signaling pathway, ensuring synchronized activation during stress conditions. SESN2 also regulated stress-activated MAPK pathways, diminishing P38 and ERK1/2 activation upon MGO exposure. This study highlights SESN2 as a pivotal regulator of endothelial cell homeostasis and angiogenic activity under MGO-induced stress, indicating its potential as a therapeutic target for addressing diabetic vascular complications and improving patient outcomes.

This study examines the association between serum Sestrin2 (SESN2) levels and cardiovascular disease (CVD) risk factors in healthy and diabetic adults, using data from the Qatar Biobank (QBB). A total of 844 participants were included, with 518 in the diabetic cohort and 326 in the healthy cohort. Clinical characteristics, cardiometabolic markers, and SESN2 levels were measured, and binomial logistic regression analyses were conducted to assess the associations between SESN2 and various health indices. Diabetic patients had significantly lower SESN2 levels compared to healthy controls (5.49 ± 5.94 vs 8.25 ± 7.57 ng/mL, P < 0.001). A significant negative correlation was observed between SESN2 and HbA1c (−0.19, P = 0.0006), insulin (−0.19, P = 0.0006), HOMA-IR (−0.17, P = 0.0024), C-peptide (−0.18, P = 0.0012), triglycerides (TG)/HDL ratio (−0.12, P = 0.0283), and the pulsatility index (PI) (−0.15, P = 0.006). In healthy individuals, higher SESN2 levels were associated with lower odds of elevated HbA1c (adjusted odds ratio [AOR] = 0.33, P = 0.00), insulin (AOR = 0.23, P = 0.00), HOMA-IR (AOR = 0.58, P = 0.06), C-peptide (AOR = 0.56, P = 0.04), and TG (AOR = 0.37, P = 0.03). In contrast, diabetic patients showed a positive correlation between SESN2 and insulin (0.15, P = 0.0005), HOMA-IR (0.11, P = 0.0106), and C-peptide (0.12, P = 0.0048). Participants in the highest SESN2 tertile had increased risks for high BMI (AOR = 1.96, P = 0.05), high TG (AOR = 1.57, P = 0.04), high NT-proBNP (AOR = 7.27, P = 0.01), and high fibrinogen (AOR = 1.92, P = 0.03). These findings suggest that while high SESN2 levels are cardioprotective in healthy individuals, they may indicate higher cellular stress in diabetics. Determining optimal SESN2 levels could help assess CVD risk, particularly in diabetic patients.

Introduction: Metabolic syndrome (MetS) poses a substantial health risk, particularly in Qatar. This study aimed to compare the diagnostic accuracy of various indices for MetS identification in a well-characterized Qatari cohort from Qatar Biobank (QBB). Methods: This cross-sectional study included 692 adults (≥18 years) from the QBB, categorized into MetS and healthy groups using the International Diabetes Federation (IDF) criteria. We compared the distributions of biochemical, anthropometric, and combined indices between groups. Logistic regression assessed associations with MetS, adjusting for demographics. Receiver Operating Characteristic (ROC) analysis evaluated discriminative performance and identified optimal thresholds. Robustness was tested using a 75/25 train-test split. Stratified analyses examined the influence of age, gender, and nationality. Results: The MetS prevalence was 19.1% among participants. Individuals with MetS displayed significantly higher levels of all indices compared to the healthy group. Triglycerides (adjusted odd ratio (AOR): 4.93), waist circumference (AOR: 3.87), and lipid accumulation product (LAP) (AOR: 14.91) showed the strongest associations within their respective categories. LAP achieved the highest discriminative performance (area under the curve (AUC): 0.896; 95% CI: 0.870–0.923), followed by the visceral adiposity index (VAI) (AUC: 0.877) and TyG × waist circumference (AUC: 0.872). LAP’s optimal threshold was 37.1, with a sensitivity of 0.856 and a specificity of 0.789. Combined indices consistently outperformed individual measures. Discriminative accuracy was comparable across genders and nationalities but higher in individuals under 45 years. Conclusion: Combined indices, particularly LAP, demonstrate superior discriminative ability for MetS in this Qatari cohort. Incorporating LAP into routine clinical practice could improve MetS detection and facilitate timely interventions. Further validation in larger, diverse populations is, however, warranted.