Abstract
NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.
Highlights
Type 2 diabetes (T2D) is a metabolic disease, characterized by hyperglycemia, which often coincides with macro- and micro-vascular complications
Others demonstrated that H2O2 is the main reactive oxygen species (ROS) product derived from NOX4 regardless of intracellular location [109], and transgenic overexpression of NOX4 in mouse endothelium leads to significant elevations of H2O2 without altering superoxide levels detected via a high-performance liquid chromatography (HPLC)-based method or the expression of SOD1, 2, and 3 isoforms [114]
It is clear that hyperglycemia and T2D are strong stimulators of NOX1- and NOX2dependent endothelial dysfunction
Summary
Type 2 diabetes (T2D) is a metabolic disease, characterized by hyperglycemia, which often coincides with macro- and micro-vascular complications. The vascular endothelium is an active endocrine organ involved in the regulation of vascular tone and maintenance of vascular homeostasis This monolayer of tissue lines the inner wall of blood vessels, positioning endothelial cells in direct contact with the flowing blood and resultant shear stress. Skeletal muscle accounts for approximately 80% of insulin-stimulated glucose disposal [12], and the hemodynamic forces due to shear stress augment insulin’s vasodilatory actions [13]; the endothelium is a critical factor in mediating the links between vascular function and metabolic demands. This review will present the normal healthy mechanisms involved in generation of nitric oxide (NO) and highlight the recent progress in understanding the contributions of hyperglycemia-induced NOX activation in endothelial dysfunction, with a focus on the interplay between NOX and eNOS. We will describe the interactions between endothelial NOX and maintenance of glucose homeostasis
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