Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension
Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension
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DOI：
10.1161/circulationaha.120.047626
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发表时间：
2020-10-13
期刊：
影响因子：
37.8
通讯作者：
Bonnet, Sebastien
中科院分区：
文献类型：
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作者：
Omura, Junichi;Habbout, Karima;Bonnet, Sebastien
背景：右心室（RV）功能是肺动脉高压（PAH）患者功能容量和生存的主要决定因素。尽管保存右心室功能的临床重要性得到公认，但控制从代偿状态到失代偿状态转变的亚细胞机制仍然知之甚少，因此临床上没有针对右心室衰竭的治疗方法，也缺乏临床有用的生物标志物。越来越多的证据表明，长链非编码rna是心脏发育和疾病的强大调节剂。尽管如此，它们在PAH不良RV重构中的意义尚不清楚。方法：根据临床病史和心脏指数，将右心室分为对照右心室、代偿性右心室和失代偿性右心室，采用定量PCR方法检测长链非编码RNA H19在患者血浆和右心室中的表达。在模拟RV衰竭的2种大鼠模型中，即单核碱和肺动脉束带，探讨了使用GapmeR抑制H19的影响。超声心动图、血流动力学、组织学和生化分析。在大鼠心肌细胞中进行了体外功能增加和功能丧失实验。结果：我们证实H19在PAH患者失代偿的RV中表达上调，并与RV肥大和纤维化相关。同样的结果也出现在单根碱和肺动脉束带大鼠身上。我们发现沉默H19抑制了病理性右心室肥大、纤维化和毛细血管稀薄，从而在不影响肺血管重塑的情况下保留了单肽大鼠和肺动脉带状带大鼠的右心室功能。这种心脏保护作用伴随着E2F转录因子1介导的zeste同源物2增强子的上调。在体外实验中，H19的下调抑制了苯肾上腺素诱导的心肌细胞肥大，而其过表达则有相反的作用。最后，我们在2个独立的特发性PAH队列中证明了血浆循环H19水平可以区分PAH患者和对照组，与RV功能相关，并预测长期生存。此外，当H19水平与NT-proBNP （n端前b型利钠肽）水平或REVEAL（早期和长期PAH疾病管理评估登记）和2015年欧洲肺动脉高压指南提出的风险评分相结合时，H19水平描绘了预后不同的患者亚组。结论：我们的研究结果确定H19是一个新的治疗靶点，可以阻止RV不适应重构的发展，也是一个有希望的PAH严重程度和预后的生物标志物。
Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.