Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension

Jiwang Chen, Justin R. Sysol, Sunit Singla, Shuangping Zhao, Aya Yamamura, Daniela Valdez-Jasso, Taimur Abbasi, Krystyna M. Shioura, Sakshi Sahni, Vamsi Reddy, Arvind Sridhar, Hui Gao, Jaime Torres, Sara M. Camp, Haiyang Tang, Shui Qing Ye, Suzy Comhair, Raed Dweik, Paul Hassoun, Jason YuanJoe GN Garcia, Roberto F. Machado

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

BACKGROUND—: Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT), is a cytozyme which regulates intracellular NAD 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. METHODS—: Plasma and mRNA and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells (PAECs) from PAH patients, as well as in lungs of rodent models of pulmonary hypertension (PH). Nampt mice were exposed 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 PH. The effects on NAMPT activity on proliferation, migration, apoptosis and calcium signaling were tested in human pulmonary artery smooth muscle cell (hPASMC). RESULTS—: Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells (PAECs) from PAH patients, as well as in lungs of rodent models of pulmonary hypertension (PH). Nampt mice were protected from hypoxia-mediated PH. NAMPT activity promoted human pulmonary artery smooth muscle cell (hPASMC) proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated hPASMC proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Finally, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia induced PH in rats. CONCLUSIONS—: Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for PAH.

Original languageEnglish (US)
JournalCirculation
DOIs
StateAccepted/In press - Feb 27 2017

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Chen, J., Sysol, J. R., Singla, S., Zhao, S., Yamamura, A., Valdez-Jasso, D., Abbasi, T., Shioura, K. M., Sahni, S., Reddy, V., Sridhar, A., Gao, H., Torres, J., Camp, S. M., Tang, H., Ye, S. Q., Comhair, S., Dweik, R., Hassoun, P., ... Machado, R. F. (Accepted/In press). Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.116.024557