Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354.

Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signalling cascade from fibroblast growth factor 2 (FGF(2)) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor nuclear factor kappaB (NF-kB) play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide (IMD-0354). Monocrotaline (MCT) was injected into 75 SpragueDawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT IMD group) or vehicle (MCT group) daily. At day 32, 65 of the MCT IMD group were alive compared with 0 of the MCT group. IMD-0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF(2), PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT IMD compared with MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF(2) in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF(2) were each markedly shortened by IMD-0354. We speculate that the positive-feedback loop (Erk1/2NF-kBMCP-1Erk1/2) is associated with progression of PAH by causing FGF(2)-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.