Jiwang Chen1, Justin R Sysol1, Sunit Singla1, Shuangping Zhao1, Aya Yamamura1, Daniela Valdez-Jasso1, Taimur Abbasi1, Krystyna M Shioura1, Sakshi Sahni1, Vamsi Reddy1, Arvind Sridhar1, Hui Gao1, Jaime Torres1, Sara M Camp1, Haiyang Tang1, Shui Q Ye1, Suzy Comhair1, Raed Dweik1, Paul Hassoun1, Jason X-J Yuan1, Joe G N Garcia2, Roberto F Machado2. 1. From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.). 2. From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.). machador@uic.edu skipgarcia@email.arizona.edu.
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.
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 Sugenhypoxia 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 Sugenhypoxia-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.
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