SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension.
SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension.
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DOI：
10.1016/j.jacbts.2020.08.010
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Chan SY
中科院分区：
文献类型：
--
作者：
Sun W;Tang Y;Tai YY;Handen A;Zhao J;Speyer G;Al Aaraj Y;Watson A;Romanelli ME;Sembrat J;Rojas M;Simon MA;Zhang Y;Lee J;Xiong Z;Dutta P;Vasamsetti SB;McNamara D;McVerry B;McTiernan CF;Sciurba FC;Kim S;Smith KA;Mazurek JA;Han Y;Vaidya A;Nouraie SM;Kelly NJ;Chan SY
在PAH患者和相关家族成员的iPSC衍生BMPR 2突变EC的公开测序数据的指导下，发现SCUBE 1在携带BMPR 2突变的EC中差异表达，依赖于HIF 1A并受PAH触发物下调。SCUBE 1缺陷控制BMPR 2相关的SMAD 1/5/9信号传导，从而调节内皮血管生成潜能、增殖和凋亡。在啮齿动物和PAH患者的血浆和肺中，SCUBE 1特异性降低，但在因左心脏病或其他急性或慢性肺和心血管疾病而患有PH的患者中则没有。定义血浆SCUBE 1临界点为5.46 ng/ml，以区分PAH与非PAH背景，具有高特异性（0.87）和显著的诊断OR（7.6）。在PAH患者中，血浆SCUBE 1水平与PA压力、肺血管阻力和RV功能障碍呈负相关。这些发现支持SCUBE 1作为PAH临床生物标志物的概念，反映了PAH的严重程度和进展，并与疾病发病机制和遗传易感性存在内在联系。利用公开的核糖核酸测序数据，我们确定SCUBE 1是一种BMPR 2相关基因，在来自携带致病性BMPR 2突变的肺动脉高压（PAH）患者和无突变的对照患者的诱导多能干细胞-内皮细胞之间差异表达。内皮SCUBE 1表达降低PAH的已知触发，其下调概括了已知的BMPR 2相关的内皮病理表型在体外。同时，从PAH啮齿动物模型和PAH患者获得的血浆中SCUBE 1浓度降低，而血浆浓度与疾病严重程度的血流动力学标志物密切相关。总之，这些数据表明SCUBE 1是PAH发病机制的新贡献者，具有潜在的治疗，诊断和预后应用。
Guided by public sequencing data of iPSC-derived BMPR2-mutant ECs derived from patients with PAH and related family members, SCUBE1 was found to be differentially expressed in ECs carrying BMPR2 mutations, dependent on HIF1A and down-regulated by PAH triggers. SCUBE1 deficiency controlled BMPR2-associated SMAD1/5/9 signaling, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with PH due to left heart disease or other acute or chronic pulmonary and cardiovascular diseases. A plasma SCUBE1 cutpoint of 5.46 ng/ml was defined to distinguish PAH from non-PAH contexts, with a high specificity (0.87) and a significant diagnostic OR (7.6). In PAH patients, plasma SCUBE1 levels negatively correlated with PA pressure, pulmonary vascular resistance, and RV dysfunction. These findings support the notion of SCUBE1 as a clinical biomarker of PAH, reflecting the severity and progression of PAH and inherently linked to disease pathogenesis and genetic predisposition. Utilizing publicly available ribonucleic acid sequencing data, we identified SCUBE1 as a BMPR2-related gene differentially expressed between induced pluripotent stem cell-endothelial cells derived from pulmonary arterial hypertension (PAH) patients carrying pathogenic BMPR2 mutations and control patients without mutations. Endothelial SCUBE1 expression was decreased by known triggers of PAH, and its down-regulation recapitulated known BMPR2-associated endothelial pathophenotypes in vitro. Meanwhile, SCUBE1 concentrations were reduced in plasma obtained from PAH rodent models and patients with PAH, whereas plasma concentrations were tightly correlated with hemodynamic markers of disease severity. Taken together, these data implicate SCUBE1 as a novel contributor to PAH pathogenesis with potential therapeutic, diagnostic, and prognostic applications.
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