Ghrelin对肺动脉内皮细胞损伤的保护作用及其与内皮舒缩分子关系的研究
摘要
目的：肺动脉高压是以肺血管重塑为主要病理特征,最终导致肺循环阻力进行性增加,右心功能衰竭,甚至死亡的一种慢性进展性疾病。它也是一处理极为棘手,高致死率和致残率的病理生理综合征,被认为是“假恶性”肿瘤。虽然目前关于肺动脉高压发病的具体机制尚未完全阐明,但大量证据表明,低氧诱导的肺动脉内皮细胞损伤及内皮依赖性舒张因子／一氧化氮(NO)分泌减少在其中起着重要作用。Ghrelin是一种已经定性清楚的肽类激素,为生长激素促分泌素受体的内源性配体。不仅具有促进生长激素的释放、促进饮食、促进胃肠蠕动、降低血压、促进细胞增殖、抑制炎症因子释放等生物学作用,而且越来越多的研究表明,Ghrelin有心血管方面的保护作用,特别是能够改善血管内皮功能。本研究旨在探讨Ghrelin对低氧诱导的人肺动脉内皮细胞(Human pulmonary artery endothelial cells, HPAEC)损伤的影响及可能的机制。
方法：HPAEC细胞株购自Cascade Biologics公司。采用HPAEC体外常氧或缺氧罐和低血清联合培养,模拟低氧微环境。HPAEC低氧微环境在AnaeroPack密闭方盒中产生,盒中置入一次性缺氧催化袋GENbox anaer(可吸收02,产生CO2),指示条监测氧的耗竭。通过外源性给予不同浓度Ghrelin或／和同时用P13K特异性抑制剂(LY294002),分别于低氧和常氧条件下培养HPAEC24h。主要观察指标：CCK-8法检测细胞活性,Tunel法和Hoechst/PI双染法检测细胞凋亡,硝酸还原酶法检测培养液NO表达水平。Western杂交法检测Akt、磷酸化Akt、mTOR、磷酸化mTOR、 eNOS、磷酸化eNOS、Bcl-2和Bax的表达。
结果：与单纯低氧相比,1×10-7mol/l Ghrelin能明显增加HPAEC细胞活性(P<0.05,n=5),上调Bcl-2/Bax比值(P<0.05,n=5),拮抗低氧诱导的HPAEC损伤。凋亡检测显示,外源性Ghrelin呈一定的浓度依赖性减轻低氧诱导的HPAEC凋亡,以1×10-7mol/l Ghrelin抗凋亡作用最显著(P<0.05,n=4)；而抑制PI3K/AKt通路可以减弱Ghrelin抗凋亡的作用。进一步,无论是在低氧,或是常氧条件下,较高浓度的外源性Ghrelin1×10-7mol/l均能明显使eNOS磷酸化水平增加,并NO合成增加。而LY294002则能显著减弱Ghrelin介导的促eNOS活化和NO分泌。
结论：研究结果表明,低氧体外培养对HPAEC的细胞活性和生长有不良影响,减少了磷酸化eNOS水平和NO分泌。外源性的Ghrelin能减轻低氧诱导的HPAEC损伤,提高细胞活性及增加NO分泌。另外,在低氧条件下,外源性Ghrelin能明显使Akt和eNOS磷酸化水平增加,提示Ghrelin可能通过激活P13K/Akt信号通路诱导了抗低氧HPAEC损伤的作用。Bcl-2/Bax比值的上调,提示Bcl-2/Bax比值在Ghrelin介导的低氧HPACE损伤保护中也有一定的作用。Ghrelin对低氧肺动脉内皮细胞损伤的保护作用,使之有可能成为治疗肺动脉高压的新药物。但其确切的作用机制以及临床意义,尚需要进一步的研究加以论证。
目的：特发性肺动脉高压(idiopathic pulmonary arterial hypertension,IPAH)是一种原因不明的以肺血管阻力增加引起肺动脉压力持续升高为特征的肺血管疾病,其发病机理不清,临床缺乏特异性症状和体征,致残率和病死率很高。肺动脉内皮功能障碍、舒张和收缩因子分泌失调在IPAH的发生和进展中发挥着重要作用。N末端脑钠肽前体(N-terminal pro-brain natriuretic peptide,NT-proBNP)由心室肌细胞合成分泌,其血浆浓度能够反映心室负荷变化,与心脏功能有良好相关性,是心力衰竭诊断的新指标。近来的研究表明,NT-proBNP与IPAH患者病情严重程度和预后呈明显相关,是IPAH预后的新指标。Ghrelin作为一种多效肽类激素,越来越多的研究表明,它有心血管方面的保护作用,包括改善心功能、舒张血管、调节血压等。研究旨在观察特发性肺动脉高压患者血浆Ghrelin水平的变化及其与NT-proBNP.内皮素1(endothlin-1,ET-1)和一氧化氮(nitric oxide,NO)的关系。
方法：首次诊断的IPAH患者20例,年龄、性别、体重质量指数相匹配的正常对照者20例。IPAH患者2011年9月至2012年8月从阜外心血管病医院19病区入选,诊断标准依据WHO肺高压临床诊断分类。排除标准：1)其他类型肺高压,如慢性血栓栓塞性肺高压；2)已经接受靶向药物治疗,如西地那非；3)慢性呼吸系统疾病,如慢性阻塞性肺病；4)左心相关的疾病,如冠心病；5)急性心衰；6)持续性心律失常,如房颤；7)其他疾病,如慢性炎症性状态,肝肾功能衰竭。收集入选对象的临床一般情况,如年龄、性别、身高、体重和病史。放免法检测血浆Ghrelin浓度；ELISA法检测血浆NT-proBNP和ET-1水平；硝酸还原酶法检测NO浓度。超声心动图检查记录肺动脉收缩压(pulmonary arterial systolic pressure,PASP)、射血分数(ejection fraction,EF)、右心室前后经(right anteroposterior ventricle diameter, RVD)、主肺动脉径(pulmonary artery trunk diameter,PAD).
结果：与正常组相比,IPAH组的患者血浆Ghrelin和NT-proBNP水平均明显升高(P<0.05)。多因素相关分析显示,在IPAH患者,血浆NT-proBNP水平与RVD (r=0.551,P=0.012)和ET-1(r=0.451,P=0.046)呈正相关。血浆Ghrelin水平与NT-proBNP(r=0.616,P=0.004).NO(r=0.464,P=0.039).RVD(r=0.485,P=0.030).PASP(r=0.591,P=0.006)之间具有良好的正相关性。进一步的多重线性回归分析表明,控制年龄、体重指数、RVD.ET-1和NO等混杂因素后,NT-proBNP (p=0.155,P=0.001).PAD(β=0.155,P=0.004).PASP(β=5.137,P=0.021)和EF(β=-9.552, P=0.038)对IPAH患者的血浆Ghrelin水平有独立预测价值(R2=76.2,P<0.001)。
结论：研究表明,在IPAH患者,血浆Ghrelin和NT-proBNP水平均明显升高。血浆Ghrelin浓度随着NT-proBNP, PASP, RVD和NO的增加而升高;而血浆NT-proBNP水平则随着RVD和ET-1的增加而升高。提示肺血管病的发生可能是体内多重拮抗效应失衡的结果。血浆Ghrelin水平的变化可能与IPAH患者的预后,甚至在IPAH的靶向治疗方面有一定的贡献。
Objectives:Pulmonary artery hypertension (PAH) is a progressive disease characterized by a sustained increase in pulmonary vascular resistance with remodeling of the pulmonary vasculature, which ultimately leads to right-sided heart failure and a high incidence of mortality. It is also considered a pseudo-malignant tumor, which is difficult to handle and with high mortality and disability. Although, the exact mechanisms underlying the pathogenesis of the PAH are yet to be fully elucidated, pulmonary artery endothelial injury and diminished endothelium-derived relaxing/nitric oxide (NO) release induced by hypoxia is thought to be a critical factor in the development of the PAH. Ghrelin (Ghr) is a well-characterized hormone identified as the natural ligand for growth hormone secretagogue receptor and has protective effects on the cardiovascular system, specifically by promoting the vascular endothelial cell function. The aim of this study was to investigate the effect of the Ghr on the hypoxia-induced injury in human pulmonary artery endothelial cells (HPAECs) and on the involved transduction pathway.
Methods:HPAECs were purchased from Cascade Biologics. HPAECs injury was induced by exposure of cells to hypoxia/serum-starving in a sealed GENbox hypoxic chamber. Effects were investigated by treating cells with varying concentrations of Ghr in the absence or presence of inhibitors that target phosphoinositide3-kinase (PI3K), in normoxic or hypoxic conditions for24h. Cell viability was determined using a cell counting kit-8assay. Apoptosis was detected using the Hochest/PI and terminal deoxynucleotidyl transferase-mediated dUTP-biotinnick end-labeling assays. The NO secreted by HPAECs was detected by nitric acid reduction method. Western blot analysis was used to examine the changes in the expression levels of endothelial nitric oxide synthase(eNOS), phospho-eNOS, phospho-Akt, Akt, mammalian target of rapamycin(mTOR), phosphor-mTOR, B-cell lymphoma-2(Bcl-2), and Bcl-2assaciated X protein (Bax).
Results:Our results indicated that the treatment with10-7mol/l Ghr significantly enhanced cell viability (P<0.05, n=5) and upregulated the ratio of Bcl-2/Bax under hypoxic condition (P<0.05, n=4), as compared with the hypoxic condition alone. However, an addition of the PI3K/Akt inhibitor LY294002inhibited these Ghr-mediated effects. Moreover, the Ghr (10-7mol/l) significantly increased NO secretion and eNOS phosphorylation in comparison with the hypoxia or normoxia alone group (P<0.05, n=4) Nevertheless, the treatment with LY294002(20μmol/l) decreased the Ghr-induced NO release as well as the eNOS activity.
Conclusions:In conclusion, we have demonstrated that Ghr could promote HPAECs survival and improve its function under hypoxic condition. We also have shown that the Ghr strongly activated Akt and eNOS, and this potentially beneficial effect of the Ghr was at least partly mediated by the PI3K/Akt pathway in these cells. The bcl-2/bax ratio was also involved in the protective action of the Ghr in HPAECs. Therefore, our findings provide a considerable therapeutic significance and indicate the clinical potential for exploiting the Ghr in the prevention and treatment of PAH characterized by endothelial dysfunction.
Objectives:Idiopathic pulmonary arterial hypertension (IPAH) is a progressive vasculopathy. Endothelial dysfunction is thought to be a critical factor in the development of IPAH. N-terminal pro-brain natriuretic peptide (NT-proBNP) has been used as a marker of ventricular dysfunction and a prognostic indicator in patients with IPAH, and Ghrelin is known to have pleiotropic effects on cardiovascular system, including improvement of myocardial function, enhancement of vasodilation and regulation of blood pressure. The aim of this study was to investigate the Ghrelin in patients with IPAH and the association of Ghrelin with NT-proBNP, endothlin-1(ET-1) and nitric oxide (NO).
Methods:This study was conducted on20patients with IPAH and20healthy controls matched for age, sex, and body mass index. IPAH patients were enrolled during a diagnostic visit in the19th ward at Fuwai Hospital from September1,2011, to August30,2012. The diagnosis of IPAH was established according to World Health Organization (WHO) pulmonary hypertension classification. Patients with one or more of the following conditions were excluded:1) other types of PH, such as chronic thromboembolic pulmonary hypertension;2) prior targeted therapy, such as sildenafil;3) chronic respiratory disorders, such as chronic obstructive pulmonary disease;4)significant LV diseases, such as coronary artery disease;5) acute heart failure;7) sustained arrhythmia, such as atrial fibrillation.8) other diseases, such as chronic inflammatory processes, renal or hepatic failure. The clinical characteristics were obtained from the patients'medical chart, such as age, sex, body weight (in kilograms), height (in meters), and medical history. Plasma Ghrelin, NT-proBNP, ET-1and NO were measured, and echocardiography was performed.
Results:Plasma Ghrelin and NT-proBNP levels were significantly higher in IPAH patients compared with values in control subjects (P<0.05). In IPAH patients, NT-proBNP levels correlated positively with RVD (r-0.551, P=0.012) and ET-1(r=0.451, P=0.046). Ghrelin levels correlated positively with NT-proBNP (r=0.616, P=0.004), NO (r=0.464, P=0.039), right ventricle diameter (RVD).(r=0.485, P=0.030) and pulmonary arterial systolic pressure (PASP)(r=0.591, P=0.006). In multiple regression analysis, the Ghrelin levels were associated with plasma NT-proBNP levels (β=0.155, P=0.001), PAD (β=0.155, P=0.004), PASP (β=5.137,P=0.021) and EF (β=-9.552, P=0.038) independent of other possible factors, such as age, BMI, RVD, ET-1and NO (R2=76.2,P<0.001).
Conclusions:In conclusion, plasma Ghrelin levels were elevated in IPAH. Increased Ghrelin levels correlated positively with NT-proBNP, PASP, RVD and NO; and plasma NT-proBNP levels correlated positively with RVD and ET-1. These results suggested that pulmonary vascular pathology is a complex imbalance of the opposing forces. Ghrelin may not only provide a novel prognostic biomarker for the IPAH, but also be a potential new therapeutic strategy.
方法：HPAEC细胞株购自Cascade Biologics公司。采用HPAEC体外常氧或缺氧罐和低血清联合培养,模拟低氧微环境。HPAEC低氧微环境在AnaeroPack密闭方盒中产生,盒中置入一次性缺氧催化袋GENbox anaer(可吸收02,产生CO2),指示条监测氧的耗竭。通过外源性给予不同浓度Ghrelin或／和同时用P13K特异性抑制剂(LY294002),分别于低氧和常氧条件下培养HPAEC24h。主要观察指标：CCK-8法检测细胞活性,Tunel法和Hoechst/PI双染法检测细胞凋亡,硝酸还原酶法检测培养液NO表达水平。Western杂交法检测Akt、磷酸化Akt、mTOR、磷酸化mTOR、 eNOS、磷酸化eNOS、Bcl-2和Bax的表达。
结果：与单纯低氧相比,1×10-7mol/l Ghrelin能明显增加HPAEC细胞活性(P<0.05,n=5),上调Bcl-2/Bax比值(P<0.05,n=5),拮抗低氧诱导的HPAEC损伤。凋亡检测显示,外源性Ghrelin呈一定的浓度依赖性减轻低氧诱导的HPAEC凋亡,以1×10-7mol/l Ghrelin抗凋亡作用最显著(P<0.05,n=4)；而抑制PI3K/AKt通路可以减弱Ghrelin抗凋亡的作用。进一步,无论是在低氧,或是常氧条件下,较高浓度的外源性Ghrelin1×10-7mol/l均能明显使eNOS磷酸化水平增加,并NO合成增加。而LY294002则能显著减弱Ghrelin介导的促eNOS活化和NO分泌。
结论：研究结果表明,低氧体外培养对HPAEC的细胞活性和生长有不良影响,减少了磷酸化eNOS水平和NO分泌。外源性的Ghrelin能减轻低氧诱导的HPAEC损伤,提高细胞活性及增加NO分泌。另外,在低氧条件下,外源性Ghrelin能明显使Akt和eNOS磷酸化水平增加,提示Ghrelin可能通过激活P13K/Akt信号通路诱导了抗低氧HPAEC损伤的作用。Bcl-2/Bax比值的上调,提示Bcl-2/Bax比值在Ghrelin介导的低氧HPACE损伤保护中也有一定的作用。Ghrelin对低氧肺动脉内皮细胞损伤的保护作用,使之有可能成为治疗肺动脉高压的新药物。但其确切的作用机制以及临床意义,尚需要进一步的研究加以论证。
目的：特发性肺动脉高压(idiopathic pulmonary arterial hypertension,IPAH)是一种原因不明的以肺血管阻力增加引起肺动脉压力持续升高为特征的肺血管疾病,其发病机理不清,临床缺乏特异性症状和体征,致残率和病死率很高。肺动脉内皮功能障碍、舒张和收缩因子分泌失调在IPAH的发生和进展中发挥着重要作用。N末端脑钠肽前体(N-terminal pro-brain natriuretic peptide,NT-proBNP)由心室肌细胞合成分泌,其血浆浓度能够反映心室负荷变化,与心脏功能有良好相关性,是心力衰竭诊断的新指标。近来的研究表明,NT-proBNP与IPAH患者病情严重程度和预后呈明显相关,是IPAH预后的新指标。Ghrelin作为一种多效肽类激素,越来越多的研究表明,它有心血管方面的保护作用,包括改善心功能、舒张血管、调节血压等。研究旨在观察特发性肺动脉高压患者血浆Ghrelin水平的变化及其与NT-proBNP.内皮素1(endothlin-1,ET-1)和一氧化氮(nitric oxide,NO)的关系。
方法：首次诊断的IPAH患者20例,年龄、性别、体重质量指数相匹配的正常对照者20例。IPAH患者2011年9月至2012年8月从阜外心血管病医院19病区入选,诊断标准依据WHO肺高压临床诊断分类。排除标准：1)其他类型肺高压,如慢性血栓栓塞性肺高压；2)已经接受靶向药物治疗,如西地那非；3)慢性呼吸系统疾病,如慢性阻塞性肺病；4)左心相关的疾病,如冠心病；5)急性心衰；6)持续性心律失常,如房颤；7)其他疾病,如慢性炎症性状态,肝肾功能衰竭。收集入选对象的临床一般情况,如年龄、性别、身高、体重和病史。放免法检测血浆Ghrelin浓度；ELISA法检测血浆NT-proBNP和ET-1水平；硝酸还原酶法检测NO浓度。超声心动图检查记录肺动脉收缩压(pulmonary arterial systolic pressure,PASP)、射血分数(ejection fraction,EF)、右心室前后经(right anteroposterior ventricle diameter, RVD)、主肺动脉径(pulmonary artery trunk diameter,PAD).
结果：与正常组相比,IPAH组的患者血浆Ghrelin和NT-proBNP水平均明显升高(P<0.05)。多因素相关分析显示,在IPAH患者,血浆NT-proBNP水平与RVD (r=0.551,P=0.012)和ET-1(r=0.451,P=0.046)呈正相关。血浆Ghrelin水平与NT-proBNP(r=0.616,P=0.004).NO(r=0.464,P=0.039).RVD(r=0.485,P=0.030).PASP(r=0.591,P=0.006)之间具有良好的正相关性。进一步的多重线性回归分析表明,控制年龄、体重指数、RVD.ET-1和NO等混杂因素后,NT-proBNP (p=0.155,P=0.001).PAD(β=0.155,P=0.004).PASP(β=5.137,P=0.021)和EF(β=-9.552, P=0.038)对IPAH患者的血浆Ghrelin水平有独立预测价值(R2=76.2,P<0.001)。
结论：研究表明,在IPAH患者,血浆Ghrelin和NT-proBNP水平均明显升高。血浆Ghrelin浓度随着NT-proBNP, PASP, RVD和NO的增加而升高;而血浆NT-proBNP水平则随着RVD和ET-1的增加而升高。提示肺血管病的发生可能是体内多重拮抗效应失衡的结果。血浆Ghrelin水平的变化可能与IPAH患者的预后,甚至在IPAH的靶向治疗方面有一定的贡献。
Objectives:Pulmonary artery hypertension (PAH) is a progressive disease characterized by a sustained increase in pulmonary vascular resistance with remodeling of the pulmonary vasculature, which ultimately leads to right-sided heart failure and a high incidence of mortality. It is also considered a pseudo-malignant tumor, which is difficult to handle and with high mortality and disability. Although, the exact mechanisms underlying the pathogenesis of the PAH are yet to be fully elucidated, pulmonary artery endothelial injury and diminished endothelium-derived relaxing/nitric oxide (NO) release induced by hypoxia is thought to be a critical factor in the development of the PAH. Ghrelin (Ghr) is a well-characterized hormone identified as the natural ligand for growth hormone secretagogue receptor and has protective effects on the cardiovascular system, specifically by promoting the vascular endothelial cell function. The aim of this study was to investigate the effect of the Ghr on the hypoxia-induced injury in human pulmonary artery endothelial cells (HPAECs) and on the involved transduction pathway.
Methods:HPAECs were purchased from Cascade Biologics. HPAECs injury was induced by exposure of cells to hypoxia/serum-starving in a sealed GENbox hypoxic chamber. Effects were investigated by treating cells with varying concentrations of Ghr in the absence or presence of inhibitors that target phosphoinositide3-kinase (PI3K), in normoxic or hypoxic conditions for24h. Cell viability was determined using a cell counting kit-8assay. Apoptosis was detected using the Hochest/PI and terminal deoxynucleotidyl transferase-mediated dUTP-biotinnick end-labeling assays. The NO secreted by HPAECs was detected by nitric acid reduction method. Western blot analysis was used to examine the changes in the expression levels of endothelial nitric oxide synthase(eNOS), phospho-eNOS, phospho-Akt, Akt, mammalian target of rapamycin(mTOR), phosphor-mTOR, B-cell lymphoma-2(Bcl-2), and Bcl-2assaciated X protein (Bax).
Results:Our results indicated that the treatment with10-7mol/l Ghr significantly enhanced cell viability (P<0.05, n=5) and upregulated the ratio of Bcl-2/Bax under hypoxic condition (P<0.05, n=4), as compared with the hypoxic condition alone. However, an addition of the PI3K/Akt inhibitor LY294002inhibited these Ghr-mediated effects. Moreover, the Ghr (10-7mol/l) significantly increased NO secretion and eNOS phosphorylation in comparison with the hypoxia or normoxia alone group (P<0.05, n=4) Nevertheless, the treatment with LY294002(20μmol/l) decreased the Ghr-induced NO release as well as the eNOS activity.
Conclusions:In conclusion, we have demonstrated that Ghr could promote HPAECs survival and improve its function under hypoxic condition. We also have shown that the Ghr strongly activated Akt and eNOS, and this potentially beneficial effect of the Ghr was at least partly mediated by the PI3K/Akt pathway in these cells. The bcl-2/bax ratio was also involved in the protective action of the Ghr in HPAECs. Therefore, our findings provide a considerable therapeutic significance and indicate the clinical potential for exploiting the Ghr in the prevention and treatment of PAH characterized by endothelial dysfunction.
Objectives:Idiopathic pulmonary arterial hypertension (IPAH) is a progressive vasculopathy. Endothelial dysfunction is thought to be a critical factor in the development of IPAH. N-terminal pro-brain natriuretic peptide (NT-proBNP) has been used as a marker of ventricular dysfunction and a prognostic indicator in patients with IPAH, and Ghrelin is known to have pleiotropic effects on cardiovascular system, including improvement of myocardial function, enhancement of vasodilation and regulation of blood pressure. The aim of this study was to investigate the Ghrelin in patients with IPAH and the association of Ghrelin with NT-proBNP, endothlin-1(ET-1) and nitric oxide (NO).
Methods:This study was conducted on20patients with IPAH and20healthy controls matched for age, sex, and body mass index. IPAH patients were enrolled during a diagnostic visit in the19th ward at Fuwai Hospital from September1,2011, to August30,2012. The diagnosis of IPAH was established according to World Health Organization (WHO) pulmonary hypertension classification. Patients with one or more of the following conditions were excluded:1) other types of PH, such as chronic thromboembolic pulmonary hypertension;2) prior targeted therapy, such as sildenafil;3) chronic respiratory disorders, such as chronic obstructive pulmonary disease;4)significant LV diseases, such as coronary artery disease;5) acute heart failure;7) sustained arrhythmia, such as atrial fibrillation.8) other diseases, such as chronic inflammatory processes, renal or hepatic failure. The clinical characteristics were obtained from the patients'medical chart, such as age, sex, body weight (in kilograms), height (in meters), and medical history. Plasma Ghrelin, NT-proBNP, ET-1and NO were measured, and echocardiography was performed.
Results:Plasma Ghrelin and NT-proBNP levels were significantly higher in IPAH patients compared with values in control subjects (P<0.05). In IPAH patients, NT-proBNP levels correlated positively with RVD (r-0.551, P=0.012) and ET-1(r=0.451, P=0.046). Ghrelin levels correlated positively with NT-proBNP (r=0.616, P=0.004), NO (r=0.464, P=0.039), right ventricle diameter (RVD).(r=0.485, P=0.030) and pulmonary arterial systolic pressure (PASP)(r=0.591, P=0.006). In multiple regression analysis, the Ghrelin levels were associated with plasma NT-proBNP levels (β=0.155, P=0.001), PAD (β=0.155, P=0.004), PASP (β=5.137,P=0.021) and EF (β=-9.552, P=0.038) independent of other possible factors, such as age, BMI, RVD, ET-1and NO (R2=76.2,P<0.001).
Conclusions:In conclusion, plasma Ghrelin levels were elevated in IPAH. Increased Ghrelin levels correlated positively with NT-proBNP, PASP, RVD and NO; and plasma NT-proBNP levels correlated positively with RVD and ET-1. These results suggested that pulmonary vascular pathology is a complex imbalance of the opposing forces. Ghrelin may not only provide a novel prognostic biomarker for the IPAH, but also be a potential new therapeutic strategy.
引文
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