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 X.J. Yuan & 2 others Joe G.N. Garcia, Roberto Machado

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Pulmonary 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. Methods: Plasma, 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. Results: Plasma 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. Conclusions: Our 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.

Original languageEnglish (US)
Pages (from-to)1532-1546
Number of pages15
JournalCirculation
Volume135
Issue number16
DOIs
StatePublished - Apr 18 2017
Externally publishedYes

Fingerprint

Nicotinamide Phosphoribosyltransferase
Pulmonary Hypertension
Lung
Pulmonary Artery
Monocrotaline
Smooth Muscle Myocytes
Therapeutics
Cell Proliferation
Blood Proteins
Rodentia
Endothelial Cells
Vascular Remodeling
Apoptosis
Messenger RNA
Histone Deacetylases
Calcium Signaling
Therapeutic Uses
Human Activities
NAD
Oxidation-Reduction

Keywords

  • hypertension, pulmonary
  • vascular remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension. / Chen, Jiwang; Sysol, Justin R.; Singla, Sunit; Zhao, Shuangping; Yamamura, Aya; Valdez-Jasso, Daniela; Abbasi, Taimur; Shioura, Krystyna M.; Sahni, Sakshi; Reddy, Vamsi; Sridhar, Arvind; Gao, Hui; Torres, Jaime; Camp, Sara M.; Tang, Haiyang; Qing Ye, Shui; Comhair, Suzy; Dweik, Raed; Hassoun, Paul; Yuan, Jason X.J.; Garcia, Joe G.N.; Machado, Roberto.

In: Circulation, Vol. 135, No. 16, 18.04.2017, p. 1532-1546.

Research output: Contribution to journalArticle

Chen, J, Sysol, JR, Singla, S, Zhao, S, Yamamura, A, Valdez-Jasso, D, Abbasi, T, Shioura, KM, Sahni, S, Reddy, V, Sridhar, A, Gao, H, Torres, J, Camp, SM, Tang, H, Qing Ye, S, Comhair, S, Dweik, R, Hassoun, P, Yuan, JXJ, Garcia, JGN & Machado, R 2017, 'Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension', Circulation, vol. 135, no. 16, pp. 1532-1546. https://doi.org/10.1161/CIRCULATIONAHA.116.024557
Chen, Jiwang ; Sysol, Justin R. ; Singla, Sunit ; Zhao, Shuangping ; Yamamura, Aya ; Valdez-Jasso, Daniela ; Abbasi, Taimur ; Shioura, Krystyna M. ; Sahni, Sakshi ; Reddy, Vamsi ; Sridhar, Arvind ; Gao, Hui ; Torres, Jaime ; Camp, Sara M. ; Tang, Haiyang ; Qing Ye, Shui ; Comhair, Suzy ; Dweik, Raed ; Hassoun, Paul ; Yuan, Jason X.J. ; Garcia, Joe G.N. ; Machado, Roberto. / Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension. In: Circulation. 2017 ; Vol. 135, No. 16. pp. 1532-1546.
@article{9d5fc60e8bce44169b80bbe96f43f921,
title = "Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension",
abstract = "Background: Pulmonary 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. Methods: Plasma, 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. Results: Plasma 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. Conclusions: Our 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.",
keywords = "hypertension, pulmonary, vascular remodeling",
author = "Jiwang Chen and Sysol, {Justin R.} and Sunit Singla and Shuangping Zhao and Aya Yamamura and Daniela Valdez-Jasso and Taimur Abbasi and Shioura, {Krystyna M.} and Sakshi Sahni and Vamsi Reddy and Arvind Sridhar and Hui Gao and Jaime Torres and Camp, {Sara M.} and Haiyang Tang and {Qing Ye}, Shui and Suzy Comhair and Raed Dweik and Paul Hassoun and Yuan, {Jason X.J.} and Garcia, {Joe G.N.} and Roberto Machado",
year = "2017",
month = "4",
day = "18",
doi = "10.1161/CIRCULATIONAHA.116.024557",
language = "English (US)",
volume = "135",
pages = "1532--1546",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "16",

}

TY - JOUR

T1 - Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension

AU - Chen, Jiwang

AU - Sysol, Justin R.

AU - Singla, Sunit

AU - Zhao, Shuangping

AU - Yamamura, Aya

AU - Valdez-Jasso, Daniela

AU - Abbasi, Taimur

AU - Shioura, Krystyna M.

AU - Sahni, Sakshi

AU - Reddy, Vamsi

AU - Sridhar, Arvind

AU - Gao, Hui

AU - Torres, Jaime

AU - Camp, Sara M.

AU - Tang, Haiyang

AU - Qing Ye, Shui

AU - Comhair, Suzy

AU - Dweik, Raed

AU - Hassoun, Paul

AU - Yuan, Jason X.J.

AU - Garcia, Joe G.N.

AU - Machado, Roberto

PY - 2017/4/18

Y1 - 2017/4/18

N2 - Background: Pulmonary 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. Methods: Plasma, 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. Results: Plasma 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. Conclusions: Our 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.

AB - Background: Pulmonary 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. Methods: Plasma, 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. Results: Plasma 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. Conclusions: Our 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.

KW - hypertension, pulmonary

KW - vascular remodeling

UR - http://www.scopus.com/inward/record.url?scp=85014005100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014005100&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.116.024557

DO - 10.1161/CIRCULATIONAHA.116.024557

M3 - Article

VL - 135

SP - 1532

EP - 1546

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 16

ER -