Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial dysfunction and cardiovascular disease. Unlike other anti-diabetic approaches, genetic deletion or pharmacological inhibition of PTP1B was found to improve glucose homeostasis and insulin signaling without causing lipid buildup in the liver, which represents an advantage over existing therapies. Furthermore, PTP1B was reported to contribute to cardiovascular disturbances, at various molecular levels, which places this enzyme as a unique single therapeutic target for both diabetes and cardiovascular disorders. Synthesizing selective small molecule inhibitors for PTP1B is faced with multiple challenges linked to its similarity of sequence with other PTPs; however, overcoming these challenges would pave the way for novel approaches to treat diabetes and its concurrent cardiovascular complications. In this review article, we summarized the major roles of PTP1B in cardiovascular disease with special emphasis on endothelial dysfunction and its interplay with insulin resistance. Furthermore, we discussed some of the major challenges hindering the synthesis of selective inhibitors for PTP1B.

Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.

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.

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.