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Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension.

ABSTRACT: Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH.

SUBMITTER: Pullamsetti SS

PROVIDER: S-EPMC5919797 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension.

Pullamsetti Soni Savai SS Seeger Werner W Savai Rajkumar R

The Journal of clinical investigation 20180409 5

Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 si ...[more]

PMID: 29629898

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Project description:BackgroundPulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension.MethodsPlasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension. Nampt+/- mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells.ResultsPlasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension. Nampt+/- mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia-induced pulmonary hypertension in rats.ConclusionsOur data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

Dataset Information

Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension.

Publications

Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension.

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