title: Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase: Influence of Exercise Training.
abstract: 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 the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality.
  
  
  
  Young, sedentary men and women were divided into lean (body mass index 18-25; n=14), intermediate (body mass index 28-32.5; n=13), and obese (body mass index 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 with 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 inhibitor, lowered (normalized) H2O2and superoxide levels, and reversed microvascular endothelial dysfunction in obese subjects. After 8 weeks of exercise, H2O2levels 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 NADPH oxidase subunits p22phox, p47phox, and p67phoxwas increased in obese relative to lean subjects, where p22phoxand p67phoxexpression was attenuated by exercise training in obese subjects.
  
  
  
  This study implicates NADPH oxidase as a source of excessive ROS production in skeletal muscle of obese individuals and links excessive NADPH oxidase-derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these maladies.
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.). jlafavo3@jhmi.edu.
authors.forename: Justin D
authors.initials: JD
authors.lastname: La Favor
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Dubis
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Joseph D
authors.initials: JD
authors.lastname: White
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Margaret A M
authors.initials: MA
authors.lastname: Nelson
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
authors.affiliation: From the Human Performance Laboratory, Departments of Kinesiology (J.D.L.F., G.S.D., H.Y., J.D.W., R.C.H.), Pharmacology and Toxicology (M.A.M.N., E.J.A.), Physiology (R.C.H.), East Carolina Diabetes and Obesity Institute (J.D.L.F., M.A.M.N., E.J.A., R.C.H.), Center for Health Disparities (R.C.H.), East Carolina University, Greenville, NC; Department of Urology, The James Buchannan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD (J.D.L.F.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City (E.J.A.); and Department of Biokinetics, Exercise and Leisure Science, University of KwaZulu-Natal, Durban, South Africa (R.C.H.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hickner
mesh_terms: D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015444:Exercise; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D055806:Microvessels / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009765:Obesity / Q000175:diagnosis / Q000201:enzymology* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D052097:Quadriceps Muscle / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology; D012039:Regional Blood Flow; D057185:Sedentary Behavior; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D014665:Vasodilator Agents; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C086986:CYBA protein, human; C527764:NCF2 protein, human; C060505:neutrophil cytosolic factor 1
keywords: acetylcholine; hydrogen peroxide; microdialysis; obesity; superoxide