title: Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt.
abstract: Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.
authors.affiliation: Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kiss
authors.affiliation: Department of Pathology, University of Pécs, Pécs, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: Heart Institute, University of Pécs, Pécs, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Komocsi
authors.affiliation: Heart Institute, University of Pécs, Pécs, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Tornyos
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Zalan
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary; MTA-PTE Nuclear-Mitochondrial Research Group, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004789:Enzyme Activation; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases