Abstract 11420: Novel Selective Nf-kb Inhibitor Compound Suppresses Pulmonary Arterial Smooth Muscle Cell Proliferation For Pulmonary Arterial Hypertension
Background; Pulmonary arterial hypertension (PAH) is characterized by elevation of PA pressure leads to right heart failure. Vascular inflammation and proliferation of cell are associated with PAH progression. We assessed the hypothesis that NFκB pathway might play a crucial role in PAH.
Methods; In rats monocrotaline (MCT)-induced PH model, we administered novel compound, selective NFκB inhibitor, IMD-0354 at 14 days after administration of MCT that PA pressure had already elevated enough. We checked survival rate at 30 days compared to MCT control (n=20, each). Echocardiography was performed on day 14 and 28. We immunohistochemically checked PA of treated and MCT rats. We analyzed mRNA expression of cytokines and other genes with PAH progress. In vitro study, PA smooth muscle cells (PASMC) proliferation stimulated with Fibroblast Growth Factor-2(FGF2) and p-65 translocation into nucleus were examined. And we analyzed pathways through FGF2 to NFkB.
Results; 70% of treatment group survived at 30 days compared to only 5% in MCT group. At 60 days, 10% of treatment group are still alive. As for echocardiography, the right ventricular dysfunction of treatment group markedly improved. In TUNEL staining, TUNEL positive cells in PA with treated rats were much higher than that of MCT group. Furthermore Bax/BCl2 ratio with treated rats was similar suggested this effect partially involved apoptosis signaling. PASMCs proliferation was suppressed by inhibition of p65 translocation and induction of apoptosis. The levels of phosphorylated ERK, phosphorylated JNK were markedly elevated by FGF2 and duration time of those levels maintained to 120 minutes. However, IMD-0354 reduced the time to 30 minutes through attenuating FGF2-induced p-65 phosphorylation.
Conclusions; Novel selective NFκB inhibitor compound can be new therapeutics for PAH with suppression of PASMCs inflammation caused by FGF2.
- © 2011 by American Heart Association, Inc.