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, Ye Shui Q, Comhair Suzy, Dweik Raed, Hassoun Paul, Yuan Jason X-J, Garcia Joe G N, Machado Roberto F
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.).
Circulation. 2017 Apr 18;135(16):1532-1546. doi: 10.1161/CIRCULATIONAHA.116.024557. Epub 2017 Feb 15.
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.
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. 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.
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. 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.
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.
肺动脉高压是一种严重的进行性疾病，其标志是肺血管重塑。烟酰胺磷酸核糖转移酶（NAMPT）是一种调节细胞内烟酰胺腺嘌呤二核苷酸水平和细胞氧化还原状态、调节组蛋白脱乙酰酶、促进细胞增殖并抑制细胞凋亡的细胞酶。我们假设NAMPT促进肺血管重塑，并且抑制NAMPT可减轻肺动脉高压。
测量肺动脉高压患者的肺组织和分离的肺动脉内皮细胞以及肺动脉高压啮齿动物模型肺组织中NAMPT的血浆、mRNA和蛋白质水平。将小鼠暴露于10%低氧和常氧环境4周，并在野百合碱和苏金低氧肺动脉高压模型中测试抑制NAMPT的预防和治疗效果。在人肺动脉平滑肌细胞中测试NAMPT活性对增殖、迁移、凋亡和钙信号传导的影响。
肺动脉高压患者的肺组织和分离的肺动脉内皮细胞以及肺动脉高压啮齿动物模型肺组织中NAMPT的血浆、mRNA和蛋白质水平均升高。小鼠免受低氧介导的肺动脉高压影响。NAMPT活性通过旁分泌作用促进人肺动脉平滑肌细胞增殖。此外，重组NAMPT通过增强Orai2和STIM2的表达增强储存性钙内流，从而刺激人肺动脉平滑肌细胞增殖。最后，抑制NAMPT活性可减轻大鼠野百合碱和苏金低氧诱导的肺动脉高压。
我们的数据提供了证据，表明NAMPT在肺血管重塑中起作用，并且抑制NAMPT可能是肺动脉高压的潜在治疗靶点。
