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

Tamas Kiss, Krisztina Kovacs, A. Komócsi, Adrienn Tornyos, Petra Zalan, B. Sümegi, F. Gallyas

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article numbere104890
JournalPLoS One
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 18 2014

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chemokines
mitogen-activated protein kinase
Chemokines
Pulmonary Hypertension
hypertension
cytokines
Phosphotransferases
lungs
Cytokines
Chemical activation
Macrophage Inflammatory Proteins
Phosphorylation
Neutrophils
Chemotactic Factors
Lung
protective effect
neutrophils
chemoattractants
Phosphatidylinositol 3-Kinase
Monocrotaline

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt. / Kiss, Tamas; Kovacs, Krisztina; Komócsi, A.; Tornyos, Adrienn; Zalan, Petra; Sümegi, B.; Gallyas, F.

In: PLoS One, Vol. 9, No. 8, e104890, 18.08.2014.

Research output: Contribution to journalArticle

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