title: Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction.
abstract: In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial natriuretic peptide (NP) and B-type NP, with their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation.
  
  
  
  We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI.
  
  
  
  Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (knockout mice with endothelial GC-A deletion) or cGKI (knockout mice with endothelial cGKI deletion). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2 days after AMI were attenuated in knockout mice with endothelial GC-A deletion and unaltered in knockout mice with endothelial cGKI deletion. Molecular studies revealed that hypoxia and tumor necrosis factor-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase 2A (PDE2A) levels. Real-time cAMP measurements in endothelial microdomains using a novel fluorescence resonance energy transfer biosensor revealed that PDE2 mediates NP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that tumor necrosis factor-α-induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions.
  
  
  
  Hypoxia and cytokines, such as tumor necrosis factor-α, modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A, and altered cGMP/cAMP cross talk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NP/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Annett
authors.initials: A
authors.lastname: Spitzl
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Denise
authors.initials: D
authors.lastname: Mathes
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Franziska
authors.initials: F
authors.lastname: Werner
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Weirather
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Katarina
authors.initials: K
authors.lastname: Špiranec
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Katharina
authors.initials: K
authors.lastname: Röck
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kämmerer
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.affiliation: From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.). michaela.kuhn@mail.uni-wuerzburg.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D009320:Atrial Natriuretic Factor
keywords: anterior wall myocardial infarction; atrial natriuretic factor receptor A; cyclic GMP; cyclic nucleotide phosphodiesterases, type 2; endothelial cells; guanylyl cyclase A