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      Inhibition of nuclear factor-κB in the lungs prevents monocrotaline-induced pulmonary hypertension in mice.

      Hypertension
      Active Transport, Cell Nucleus, Animals, Apoptosis, genetics, physiology, Blotting, Western, Bone Morphogenetic Protein Receptors, Type II, metabolism, Cell Nucleus, Cytokines, Endothelial Cells, Gene Expression, Hypertension, Pulmonary, chemically induced, Hypertrophy, Right Ventricular, physiopathology, I-kappa B Proteins, Lung, pathology, Male, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Monocrotaline, Mutation, NF-kappa B, antagonists & inhibitors, RNA Interference, Receptors, Notch, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor RelA

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          Abstract

          Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with significant morbidity and mortality in patients with various lung and heart diseases. PAH is characterized by vascular obstruction which leads to a sustained increased pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure. Limited PAH therapies indicate that novel approaches are urgently needed for the treatment of PAH. Nuclear factor-κB (NF-κB) has been shown to play an important role in different cardiac pathologies; however, the role of NF-κB remains limited in the setting of PAH. Here, we investigated whether NF-κB inhibition in the lungs using Club (Clara) cell-10 promoter driving IκBα mutant had any effect in monocrotaline (MCT)-induced PAH mouse model. Our data revealed that MCT-induced PAH and right ventricular hypertrophy were associated with NF-κB activation, inflammatory response, and altered expression of bone morphogenetic protein receptor 2, inhibitor of differentiation, and Notch-3 signaling molecules in wild-type mice; and all these alterations were prevented in IκBα mutant mice treated with MCT. Moreover, endothelial cell apoptosis and endothelial-to-mesenchymal transition occurred in the lungs of MCT-treated wild-type mice and were restored in IκBα mutant+MCT mice, indicating an association with NF-κB signaling. In lung microvascular endothelial cells, IκBα (AA) mutant plasmid restored the decreased bone morphogenetic protein receptor 2 protein level and reversed the endothelial-to-mesenchymal transition process induced by transforming growth factor-β1. We conclude that NF-κB regulates bone morphogenetic protein receptor 2-inhibitor of differentiation-Notch-3 axis genes and the subsequent endothelial cell apoptosis and endothelial-to-mesenchymal transition events in the lungs, providing new mechanistic information about MCT-induced PAH and right ventricular hypertrophy.

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