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.

Mibefradil Suppresses the Proliferation of Pulmonary Artery Smooth Muscle Cells

“…This is in contrast to a report by Kiss et al ,20 in which sildenafil reduced ERK and p38 activation, and enhanced Akt phosphorylation in a monocrotaline-induced rat PAH model. It is possible that these inconsistencies are due to the different models employed.…”

Arginase inhibition protects against hypoxia-induced pulmonary arterial hypertension

“…Arg inhibition decreases the phosphorylation of Akt and ERK1/2. It has been reported that the Akt and ERK pathways are involved in the proliferation pfHPASMCs and progression of PAH (20). Thus, in the present study, the protein expression levels of Akt and ERK in vitro were assessed using western blot analysis.…”

Pulmonary Arterial Hypertension in a Patient with Multiple Sclerosis Treated with Interferon Beta: A Case Report

“…The prognosis of patients with the disease is poor; most untreated patients die within three years due to right-sided heart failure. The main clinical signs and symptoms of PAH include progressive dyspnea with peripheral cyanosis, chest pains, and fatigability [4]. As for our patient, progressive dyspnea and fatigability had been among her principal initial signs and symptoms of PAH before a diagnosis was made.…”

“…All clinical features are nonspecific, which is, unfortunately, a frequent cause of delayed detection of the disease [3]. Luckily, however, the incidence of this disease is low-approximately 10 patients per million people [4].…”