title: Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation.
abstract: BACKGROUND
  Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species.
  
  
  OBJECTIVE
  We examined the hypothesis that telomerase activity modulates microvascular flow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD).
  
  
  RESULTS
  Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n≥4; P<0.05). L-NAME (N(ω)-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished flow-mediated dilation in arterioles from subjects without CAD, whereas polyethylene glycol-catalase (PEG-catalase; hydrogen peroxide scavenger) had no effect. After exposure to BIBR-1532, arterioles from non-CAD subjects maintained the magnitude of dilation but changed the mediator from nitric oxide to mitochondrial hydrogen peroxide (% max diameter at 100 cm H2O: vehicle 74.6±4.1, L-NAME 37.0±2.0*, PEG-catalase 82.1±2.8; BIBR-1532 69.9±4.0, L-NAME 84.7±2.2, PEG-catalase 36.5±6.9*). Conversely, treatment of microvessels from CAD patients with the telomerase activator AGS 499 converted the PEG-catalase-inhibitable dilation to one mediated by nitric oxide (% max diameter at 100 cm H2O: adipose, AGS 499 78.5±3.9; L-NAME 10.9±17.5*; PEG-catalase 79.2±4.9). Endothelial-independent dilation was not altered with either treatment.
  
  
  CONCLUSIONS
  We have identified a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These findings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.). abeyer@mcw.edu.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Beyer
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Julie K
authors.initials: JK
authors.lastname: Freed
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Durand
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Michael
authors.initials: M
authors.lastname: Riedel
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Karima
authors.initials: K
authors.lastname: Ait-Aissa
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Paula
authors.initials: P
authors.lastname: Green
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Hockenberry
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: R Garret
authors.initials: RG
authors.lastname: Morgan
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Refael
authors.initials: R
authors.lastname: Peleg
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Mario
authors.initials: M
authors.lastname: Gasparri
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Chris K
authors.initials: CK
authors.lastname: Rokkas
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Janine H
authors.initials: JH
authors.lastname: Santos
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: Esther
authors.initials: E
authors.lastname: Priel
authors.affiliation: From the Department of Medicine, Cardiovascular Center (A.M.B., M.J.D., M.R., K.A.-A., J.C.H., D.D.G.), Department of Physiology (A.M.B., K.A.-A., D.D.G.), Department of Anesthesiology (J.K.F.), Department of Physical Medicine and Rehabilitation (M.J.D.), and Departments of Surgery, Cardiothoracic Surgery (M.G., C.K.R.), Medical College of Wisconsin, Milwaukee; Departments of Pharmacology and Physiology, New Jersey Medical School of Rutgers, Newark (P.G., J.H.S.); Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City (R.G.M., A.J.D.); and Shraga Segal Departments of Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (R.P., E.P.).
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply / Q000201:enzymology; D000368:Aged; D001160:Arterioles / Q000201:enzymology; D001783:Blood Flow Velocity / Q000502:physiology*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000201:enzymology / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D008875:Middle Aged; D019098:Telomerase / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D019098:Telomerase
keywords: coronary artery disease; flow-mediated dilation; microvascular dysfunction; mitochondria; reactive oxygen species; telomerase activity; vascular biology