Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt

• Published in: PloS one 2014-08, Vol.9 (8), p.e104890-e104890
• Main Authors: Kiss, Tamas, Kovacs, Krisztina, Komocsi, Andras, Tornyos, Adrienn, Zalan, Petra, Sumegi, Balazs, Gallyas, Jr, Ferenc
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Active Transport, Cell Nucleus - drug effects; AKT protein; Analysis; Animals; Biochemistry; Biology and life sciences; Cell activation; Cell Nucleus - metabolism; Chemokines; Chemokines - metabolism; CXC chemokines; Cytokines; Drinking water; Enzyme Activation; Extracellular signal-regulated kinase; Health aspects; Heart; Histology; Hypertension; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Hypoxia; Inflammation; Interferon; Interleukin; Interleukins; Kinases; Laboratory animals; Leukocytes (mononuclear); Lipopolysaccharides; Lung - drug effects; Lung - metabolism; Lung morphology; Lungs; Macrophage inflammatory protein; Macrophages; MAP kinase; MAP Kinase Signaling System - drug effects; Medicine and Health Sciences; Metalloproteinase; Mitogen-Activated Protein Kinases - metabolism; Monocrotaline; Morphology; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Phosphatase; Phosphorylation; Phosphotransferases; Piperazines - pharmacology; Piperazines - therapeutic use; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary arteries; Pulmonary hypertension; Purines - pharmacology; Purines - therapeutic use; Rats; Right ventricular failure; Rodents; Signaling; Sildenafil; Sildenafil Citrate; Smooth muscle; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Tissue inhibitor of metalloproteinases; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use; Veins & arteries; Ventricle; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104890

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.