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. 2014 Jun;63(6):1260-9.
doi: 10.1161/HYPERTENSIONAHA.114.03220. Epub 2014 Mar 10.

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

Li Li  1 , Chuanyu Wei, Il-Kwon Kim, Yvonne Janssen-Heininger, Sudhiranjan Gupta
Affiliations

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

Li Li et al. Hypertension. 2014 Jun.

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.

Keywords: NF-kappa B; hypertension, pulmonary; mice.

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