Wen Chen1, Annett Spitzl1, Denise Mathes1, Viacheslav O Nikolaev1, Franziska Werner1, Johannes Weirather1, Katarina Špiranec1, Katharina Röck1, Jens W Fischer1, Ulrike Kämmerer1, David Stegner1, Hideo A Baba1, Ulrich Hofmann1, Stefan Frantz1, Michaela Kuhn2. 1. 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.). 2. 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.
Abstract
RATIONALE: 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. OBJECTIVE: We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVE: We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI. METHODS AND RESULTS: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. CONCLUSIONS: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: Hannah Fish-Trotter; Jane F Ferguson; Nirav Patel; Pankaj Arora; Norrina B Allen; Katherine N Bachmann; Lori B Daniels; Muredach P Reilly; Joao A C Lima; Thomas J Wang; Deepak K Gupta Journal: Circ Heart Fail Date: 2020-06-08 Impact factor: 8.790
Authors: Madhu V Singh; Michael Z Cicha; Sarah Nunez; David K Meyerholz; Mark W Chapleau; François M Abboud Journal: Am J Physiol Heart Circ Physiol Date: 2019-02-22 Impact factor: 4.733