A group of researchers from the University of Pécs, Hungary, have attempted to understand the mechanism by which pulmonary vascular remodeling initiates right ventricular failure and hypoxia, one of the leading causes behind the mortality rates associated with Pulmonary Hypertension (PH).
Sildenafil, known more commonly by its brand name Viagra, is an inhibitor of phosphodiesterase type 5 (PDE-5), an enzyme found in various tissues and involved in the cardiovascular system, and is frequently used in the treatment of PH, since it can improve exercise capacity, PH symptoms, and haemodynamics. However, the molecular mechanisms behind the protective effect exerted by this drug are not fully understood.
In this study, entitled “Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt”, published in the PLOS ONE journal, the team used a monocrotaline (MCT, a toxic metabolite of plant origin)-induced rat PH model to analyze lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-kB activation, to understand the mechanisms by which sildenafil’s exerts its protective effects in PH.
The authors could observe that sildenafil not only protected lung morphology but it also suppressed several cytokines directly related with neutrophil and mononuclear cell recruitment, such as cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2a/b, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1a, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1a, and MIP-3a.
All of these cytokines induced by MCT treatment are regulated by NF-kB, and as such, through immunoblotting and immunohistochemistry with specific antibodies targeted at this nuclear factor, the authors discovered that MCT treatment caused a massive activation and nuclear translocation of NF-kB, a process significantly decreased upon sildenafil treatment.
Furthermore, sildenafil reduced the amount of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation, enhancing the activation of the cytoprotective Akt pathway in these PH mice.
Based on the results of this study, the authors concluded that, in mice, sildenafil is able to overcome the pathologic remodeling processes induced by MCT treatment, thus decreasing the infiltration of inflammatory cells and reducing edema formation.
Altogether, these data can reveal important clues regarding the novel mechanisms responsible for the beneficial effects of Viagra use in PH patients to reduce inflammation and swelling, moving one step closer to the development of improved therapies targeted at this progressive and incurable disease.