Nuclear Factor κB Inhibition Reduces Lung Vascular Lumen Obliteration in Severe Pulmonary Hypertension in Rats

Abstract

NF-κB and IL-6, a NF-κB downstream mediator, play a central role in the inflammatory response of tissues. We aimed to determine the role of the classical NF-κB pathway in severe pulmonary arterial hypertension (PAH) induced by SU5416 and chronic hypoxia (SuHx) in rats. Tissue samples from patients with idiopathic PAH (iPAH) and control subjects were investigated. SuHx rats were treated from Days 1 to 3, 1 to 21, and 29 to 42 with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and/or from Days 1 to 21 with anti-IL-6 antibody. Nuclear staining for NF-κB, an indicator of the activation of the classical NF-κB pathway, was detected in pulmonary arterial lesions of patients with iPAH and SuHx rats. NF-κB inhibition with PDTC prevented and reduced pulmonary arterial obliteration without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. PDTC treatment prevented or reduced apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration. IL-6 inhibition had only a partial effect on apoptosis and obliteration. Pulmonary arterial media wall thickness was not affected by any of these treatments. Preventive and therapeutic PDTC treatment promoted immune regulation by increasing the number of perivascular CD4(+) T cells, in particular regulatory T cells (early treatment), and by reducing the number of perivascular CD8(+) T lymphocytes and CD45RA(+) B lymphocytes. Therapeutic PDTC treatment further preserved right ventricular function in SuHx animals. Inhibition of NF-κB may represent a therapeutic option for pulmonary arterial obliteration via reduced vessel wall cell apoptosis and improved regulation of the immune system.

Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia

“…Emerging evidence suggests that the expression of miRs can be regulated at transcriptional levels [46], and NF-κB has been shown to promote miR-223-3p transcriptional induction, thus facilitating the proliferation and migration of gastric cancer cells [47]. Increased NF-κB activation was previously observed in mouse and rat lungs following hypoxia [33] or monocrotaline [27,29] stimulation. In this study, promoter analysis led to the identification of a putative NF-κB binding site located in the promoter region of the miR-335-3p gene.…”

“…The expression of miRs in response to environmental stimuli is often subjected to regulation by transcriptional factors including nuclear factor-kappa beta (NF-κB) [23][24][25][26]. NF-κB plays an essential role in the modulation of PAH [27][28][29][30][31][32], and NF-κB activation is one of the primary hypoxia-driven signals to promote pulmonary arterial obliteration, inflammation, and reduced immune regulation in the context of severe obliterative PAH [33]. Although miRs are becoming increasingly recognized as important regulators of PAH, comparatively little is known about the specific role of the NF-κB pathway in miR regulation during PAH pathogenesis.…”

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

“…Celastrol is a compound obtained from Tripterygium wilfordii and its usefulness has been reported in some inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis, and allergy (35). Celastrol suppresses the activity of NF-κB, which up-regulates inflammatory genes and enhances cardiac hypertrophy (52) and pulmonary vascular remodeling (53). As CyPA and Bsg activate NF-κB (48,54), the effect of celastrol on HF may have been due to the inhibition of CyPA/Bsg-NF-κB axis, which enhances ROS generation and inflammatory status.…”

The Roles of Immunity in the Prevention and Evolution of Pulmonary Arterial Hypertension

“…Experimental pulmonary hypertension (PH) studies have dissected various inflammatory pathways and have identified a variety of mediators of inflammation (18)(19)(20)(21)(22)(23). (By convention, preclinical models of PAH are referred to as "PH").…”

“…Animal experiments demonstrate that pharmacological and cell-based therapies can prevent or reverse established severe PAH (19,(21)(22)(23)62). New trials are beginning to test the efficacy of immunomodulatory treatments in various forms of severe PAH.…”