title: S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.
abstract: BACKGROUND
  The regulation of calcium (Ca(2+)) homeostasis by β-adrenergic receptor (βAR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the βAR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in βAR-dependent regulation of Ca(2+) handling has not yet been explicated fully.
  
  
  OBJECTIVE
  To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on βAR-dependent alterations in cardiomyocyte Ca(2+) handling and hypertrophy.
  
  
  RESULTS
  Using transgenic mice to titrate the levels of protein S-nitrosylation, we uncovered major roles for protein S-nitrosylation, in general, and for phospholamban and cardiac troponin C S-nitrosylation, in particular, in βAR-dependent regulation of Ca(2+) homeostasis. Notably, S-nitrosylation of phospholamban consequent upon βAR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca(2+)-ATPase and increases cytosolic Ca(2+) transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca(2+). During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca(2+) overload.
  
  
  CONCLUSIONS
  S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca(2+)-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca(2+) homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Tomoya
authors.initials: T
authors.lastname: Irie
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Sips
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kai
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kida
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Kohei
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirai
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Kasra
authors.initials: K
authors.lastname: Moazzami
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Pawina
authors.initials: P
authors.lastname: Jiramongkolchai
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Paschalis-Thomas
authors.initials: PT
authors.lastname: Doulias
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Antonis A
authors.initials: AA
authors.lastname: Armoundas
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kranias
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.).
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.affiliation: From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (T.I., P.Y.S., S.K., K.K., K.I., S.H., P.J., D.B.B., M.K., K.D.B., F.I.), Cardiovascular Research Center, Division of Cardiology, Department of Medicine (K.M., A.A.A., K.D.B.), and Division of Rheumatology Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.Y.S.); Children's Hospital of Philadelphia Research Institute, Department of Pediatrics and Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania (P.-T.D., H.I.); Department of Research, Shriners Hospitals for Children (M.K.) and Department of Pharmacology (E.K.), University of Cincinnati College of Medicine, OH; and Institute for Transformative Molecular Medicine, Case Western Reserve University, Harrington Discovery Institute University Hospitals, Cleveland, OH (J.S.S.). fichinose@mgh.harvard.edu.
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000445:Aldehyde Oxidoreductases; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006984:Hypertrophy; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction / Q000187:drug effects; D019210:Troponin I / Q000235:genetics / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D000445:Aldehyde Oxidoreductases; D002118:Calcium; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D009569:Nitric Oxide; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019210:Troponin I; D000099211:Phospholamban; C087006:formaldehyde dehydrogenase, glutathione-independent
keywords: beta adrenergic; calcium; heart failure; myocardial contraction; nitric oxide; receptors