Hyperketonemia (Acetoacetate) Upregulates NADPH Oxidase 4 and Elevates Oxidative Stress, ICAM-1, and Monocyte Adhesivity in Endothelial Cells

Abstract

Background/Aims: The incidence of developing microvascular dysfunction is significantly higher in type 1 diabetic (T1D) patients. Hyperketonemia (acetoacetate, β-hydroxybutyrate) is frequently found along with hyperglycemia in T1D. Whether hyperketonemia per se contributes to the excess oxidative stress and cellular injury observed in T1D is not known. Methods: HUVEC were treated with ketones in the presence or absence of high glucose for 24 h. NOX4 siRNA was used to specifically knockdown NOX4 expression in HUVEC. Results: Ketones alone or in combination with high glucose treatment cause a significant increase in oxidative stress, ICAM-1, and monocyte adhesivity to HUVEC. Using an antisense approach, we show that ketone induced increases in ROS, ICAM-1 expression, and monocyte adhesion in endothelial cells were prevented in NOX4 knockdown cells. Conclusion: This study reports that elevated levels of ketones upregulate NOX, contributing to increased oxidative stress, ICAM-1 levels, and cellular dysfunction. This provides a novel biochemical mechanism that elucidates the role of hyperketonemia in the excess cellular injury in T1D. New drugs targeting inhibition of NOX seems promising in preventing higher risk of complications associated with T1D.

Combination Therapy of Nifedipine and Sulphonylureas Exhibits a Mutual Antagonistic Effect on the Endothelial Cell Dysfunction Induced by Hyperglycemia Linked to Vascular Disease

“…Leeson et al have demonstrated that carriage of an endothelial nitric oxide synthase polymorphism was associated with functional changes in the endothelium and in cardiovascular disease [45]. Furthermore, uncoupling the endothelial nitric oxide synthase resulting in superoxide anion (O 2 -) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction [8,9,46]. It has been reported that NO preservation protected endothelial dysfunction under high glucose conditions [47].…”

Effect of procyanidine on VEGFR-2 expression and transduction pathway in rat endothelial progenitor cells under high glucose conditions

“…Several studies (Kanikarla-Marie and Jain, 2015;Liu et al, 2015;Seebacher et al, 2015;Wang et al, 2015) have reported that high glucose concentrations lead to over-aggregation of ROS in the body, which results in oxidative stress injury and affects the cell growth and survival cycle. This causes abnormal metabolism and dysfunction in cells, as well as apoptosis, ultimately resulting in diabetic vascular complications, ischemic necrosis, ischemic neuropathy, and paresthesia in the affected limbs.…”

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

“…Interestingly, NOX4 appears to be protective in the aorta as deletion or inhibition of NOX4 resulted in increased atherosclerosis associated with increased inflammation in both vascular and immune cells 37. Activation of PKC and the generation of AGEs, both of which are upregulated in the diabetic environment, have been shown to activate NOX isoforms in monocytes and macrophages, and drive an increase in the expression of pro‐inflammatory genes such as IL‐6, monocyte chemoattractant protein 1(MCP‐1), and intercellular adhesion molecule 1 (ICAM‐1) 38, 39. By activation of these pathways, it has been demonstrated that inflammation is increased throughout the body, leading to the generation of ROS.…”