Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

Abstract

Objective The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) on microvascular endothelial function in obese human subjects and to determine the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality. Approach and Results Young, sedentary men and women were divided into lean (BMI 18–25; n=14), intermediate (BMI 28–32.5; n=13), and obese (BMI 33–40; n=15) groups. A novel microdialysis technique was utilized to detect elevated interstitial hydrogen peroxide (H2O2) and superoxide levels in the vastus lateralis of obese compared to both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis via the microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascular endothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase (Nox) inhibitor, lowered (normalized) H2O2 and superoxide levels and reversed microvascular endothelial dysfunction in obese subjects. Following 8-weeks of exercise, H2O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects was restored to levels similar to lean subjects. Skeletal muscle protein expression of the Nox subunits p22phox, p47phox, and p67phox were increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuated by exercise training in obese subjects. Conclusions This study implicates Nox as a source of excessive ROS production in skeletal muscle of obese individuals, and links excessive Nox derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these maladies.

Endothelial Functions

“…With this method, they showed that NADPH oxidase-derived ROS levels were elevated in obese subjects, associated with microvascular endothelial dysfunction as evidenced by impaired acetylcholine-induced blood flow increases. 18 Notably, an 8-week aerobic exercise training normalized both the elevated ROS levels and the microvascular endothelial dysfunction in this study. 18 In striking contrast, the physiological roles of ROS in the regulation of vascular homeostasis have been brought to light.…”

“…18 Notably, an 8-week aerobic exercise training normalized both the elevated ROS levels and the microvascular endothelial dysfunction in this study. 18 In striking contrast, the physiological roles of ROS in the regulation of vascular homeostasis have been brought to light. 16 Gray et al 19 demonstrated the atheroprotective role of NADPH oxidase 4-derived hydrogen peroxide (H 2 O 2 ) in a diabetic atherosclerosis mouse model.…”

“…15,16 In line with this concept, using adipocyte-specific NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4-deficient mice, Den Hartigh et al 17 demonstrated that adipocyte NADPH oxidase 4-derived ROS contributed to the development of obesityrelated insulin resistance by triggering adipocyte inflammation. La Favor et al 18 developed a novel microdialysis technique that enables simultaneous measurement of ROS levels and microvascular endothelial functions in vivo. With this method, they showed that NADPH oxidase-derived ROS levels were elevated in obese subjects, associated with microvascular endothelial dysfunction as evidenced by impaired acetylcholine-induced blood flow increases.…”

Thrombotic Regulation From the Endothelial Cell Perspectives

“…50 ROS regulates EC biology. 37,[52][53][54][55] However, evidence on thrombosis regulation by EC-derived ROS is limited. Antioxidative treatment inhibits the release of thrombogenic TF from irradiation-and cytokinetreated ECs, indicating a significant role of endothelial ROS in thrombotic regulation.…”

Redox Control of Vascular Function

“…These data suggest that exercise and fat accumulation heavily contribute to the regulation of ROS in the vasculature through NOX protein expression in adjacent tissues. 55 …”