imd-0354 and Hypertension--Pulmonary

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 (FGF₂) 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 Sprague-Dawley 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 FGF₂, 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 FGF₂ in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF₂ were each markedly shortened by IMD-0354.. We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF₂-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

Topics: Animals; Antihypertensive Agents; Apoptosis; Benzamides; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Feedback, Physiological; Fibroblast Growth Factor 2; Hypertension, Pulmonary; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocrotaline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Tissue Plasminogen Activator; Transcription Factor RelA; Ventricular Function, Right; Ventricular Pressure