Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension.
Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension.
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DOI：
10.1161/circulationaha.116.024557
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发表时间：
2017-04-18
期刊：
影响因子：
37.8
通讯作者：
Machado RF
中科院分区：
文献类型：
--
作者：
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;Ye SQ;Comhair S;Dweik R;Hassoun P;Yuan JX;Garcia JGN;Machado RF
肺动脉高压（PAH）是一种严重的进行性疾病，其特征是肺血管重构。烟酰胺磷酸核糖基转移酶（NAMPT）是一种细胞酶，它调节细胞内NAD水平和细胞氧化还原状态，调节组蛋白脱乙酰酶，促进细胞增殖和抑制细胞凋亡。我们假设NAMPT促进肺血管重构，抑制NAMPT可以减轻肺动脉高压。在PAH患者的肺和分离的肺动脉内皮细胞（PAEC）以及肺动脉高压（PH）啮齿动物模型的肺中测量NAMPT的血浆、mRNA和蛋白水平。Nampt+/−小鼠暴露于10%低氧和空气中4周，观察NAMPT抑制剂对肺动脉高压的防治作用，以及对人肺动脉平滑肌细胞（hPASMC）增殖、迁移、凋亡和钙信号的影响。在PAH患者的肺和分离的肺动脉内皮细胞（PAEC）以及肺动脉高压（PH）啮齿动物模型的肺中，NAMPT的血浆、mRNA和蛋白水平均升高。NAMPT活性通过旁分泌效应促进人肺动脉平滑肌细胞（hPASMC）增殖。此外，重组NAMPT通过增强Orai 2和STIM 2的表达，通过增强钙池操作的钙内流来刺激hPASMC增殖。抑制NAMPT活性可减轻野百合碱和Sugen引起的大鼠肺动脉高压。我们的数据提供了证据表明NAMPT在肺血管重构中起作用，其抑制可能是PAH的潜在治疗靶点。
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. 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). 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. Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for PAH.