title: The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function.
abstract: BACKGROUND
  Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide (NO). The F-BAR protein NO synthase traffic inducer (NOSTRIN) is an interaction partner of endothelial NO synthase and modulates its subcellular localization, but the role of NOSTRIN in pathophysiology in vivo is unclear.
  
  
  OBJECTIVE
  We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on NO production and cardiovascular function in vivo using NOSTRIN knockout mice.
  
  
  RESULTS
  The levels of NO and cGMP were significantly reduced in mice with endothelial cell-specific deletion of the NOSTRIN gene resulting in diastolic heart dysfunction. In addition, systemic blood pressure was increased, and myograph measurements indicated an impaired acetylcholine-induced relaxation of isolated aortic rings and resistance arteries. We found that the muscarinic acetylcholine receptor subtype M3 (M3R) interacted directly with NOSTRIN, and the latter was necessary for correct localization of the M3R at the plasma membrane in murine aorta. In the absence of NOSTRIN, the acetylcholine-induced increase in intracellular Ca(2+) in primary endothelial cells was abolished. Moreover, the activating phosphorylation and Golgi translocation of endothelial NO synthase in response to the M3R agonist carbachol were diminished.
  
  
  CONCLUSIONS
  NOSTRIN is crucial for the localization and function of the M3R and NO production. The loss of NOSTRIN in mice leads to endothelial dysfunction, increased blood pressure, and diastolic heart failure.
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Igor
authors.initials: I
authors.lastname: Kovacevic
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Miriam
authors.initials: M
authors.lastname: Müller
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Ehrke
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Voahanginirina
authors.initials: V
authors.lastname: Randriamboavonjy
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Karin
authors.initials: K
authors.lastname: Kohlstedt
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Tanja
authors.initials: T
authors.lastname: Hindemith
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.).
authors.forename: Meike
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: From the Institute for Biochemistry II, Goethe-University Frankfurt Medical School, Frankfurt/Main, Germany (I.K., M.M., A.E., T.H., M.H., S.O.); Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany (B.K., R.T.S.); and Institute for Vascular Signalling, Goethe-University Frankfurt, Frankfurt/Main, Germany (V.R., K.K., I.F.). oess@biochem2.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Oess
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000502:physiology*; D005260:Female; D006339:Heart Rate / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D043587:Receptor, Muscarinic M3 / Q000032:analysis / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C495611:Nostrin protein, mouse; D043587:Receptor, Muscarinic M3
keywords: GTP-binding proteins; NOSTRIN protein, mouse; echocardiography; nitric oxide synthase type III; receptors, G-protein-coupled