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Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM. [ABSTRACT FROM AUTHOR]

Aims The present study was to investigate the effect of hydrogen peroxide (H 2 O 2 ) on bone marrow stem cells and their endothelial differentiation and the underlying mechanisms in vitro. Main methods Rat bone marrow multipotent adult progenitor cells (MAPCs) were used as the source of bone marrow stem cells, and treated with H 2 O 2 (with the final concentration from 0 to 50 μM) with or without N-acetylcysteine (NAC, 0.1 mM). Reactive oxygen species (ROS) was measured by electron paramagnetic resonance (EPR) and fluorescent microscope. Flow cytometry and immunoblotting were used to determine apoptosis and differentiation of MAPCs. Key findings H 2 O 2 generated a significant amount of intracellular and extracellular ROS in the culture system, substantially inhibited the proliferation of MAPCs and Oct-4 expression, and induced their apoptosis in a dose-dependent manner. Exposure to H 2 O 2 also significantly attenuated the endothelial differentiation of MAPCs with reduced expression of endothelial markers CD31 and FLK-1 as well as impaired in vitro vascular structure formation. Both intracellular and extracellular ROS production from H 2 O 2 were blocked by NAC. NAC treatment effectively prevented H 2 O 2 -induced reduction of Oct-4 expression in the cells. However, NAC treatment only partially prevented H 2 O 2 -induced apoptosis, and inhibition of cell proliferation and endothelial differentiation of MAPCs. Significance H 2 O 2 exposure suppressed Oct-4 expression in MAPCs through ROS-dependent mechanism, while increasing the apoptosis of MAPCs and inhibiting their proliferation and endothelial differentiation with a mechanism partially due to ROS generation in vitro. [ABSTRACT FROM AUTHOR]

Males have a higher risk for cardiovascular diseases (CVDs) than females. Ambient fine particulate matter (PM) exposure increases CVD risk with increased reactive oxygen species (ROS) production and oxidative stress. Endothelial progenitor cells (EPCs) are important to vascular structure and function and can contribute to the development of CVDs. The aims of the present study were to determine if sex differences exist in the effect of PM exposure on circulating EPCs in mice and, if so, whether oxidative stress plays a role. Male and female C57BL/6 mice (8–10 weeks old) were exposed to PM or a vehicle control for six weeks. ELISA analysis showed that PM exposure substantially increased the serum levels of IL-6 and IL-1β in both males and females, but the concentrations were significantly higher in males. PM exposure only increased the serum levels of TNF-α in males. Flow cytometry analysis demonstrated that ROS production was significantly increased by PM treatment in males but not in females. Similarly, the level of circulating EPCs (CD34+/CD133+ and Sca-1+/Flk-1+) was significantly decreased by PM treatment in males but not in females. Antioxidants N-acetylcysteine (NAC) effectively prevented PM exposure-induced ROS and inflammatory cytokine production and restored circulating EPC levels in male mice. In sharp contrast, circulating EPC levels remained unchanged in female mice with PM exposure, an effect that was not altered by ovariectomy. In conclusion, PM exposure selectively decreased the circulating EPC population in male mice via increased oxidative stress without a significant impact on circulating EPCs in females independent of estrogen. [ABSTRACT FROM AUTHOR]