SCUBE1: A BMPR2-Relevant Diagnostic Biomarker for PAH
- Signal peptide CUB-EGF domain-containing protein 1 (SCUBE1) is expressed and secreted from pulmonary arterial endothelial cells. In response to pulmonary arterial hypertension (PAH) triggers, including hypoxia and inflammatory factors, SCUBE1 regulates bone morphogenic protein receptor type 2 (BMPR2)-relevant pulmonary endothelial functions.
- Plasma SCUBE1 was decreased specifically in patients with PAH but not in those with pulmonary hypertension (PH) secondary to left heart dysfunction or other acute or chronic pulmonary and cardiovascular diseases. This makes SCUBE1 an applicable diagnostic biomarker in distinguishing PAH from non-PAH contexts, with a relatively high specificity of 0.87.
- Plasma SCUBE1 levels in patients with PAH negatively correlate with the severity and progression of pulmonary vascular remodeling, reflected by pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular (RV) dysfunction.
The diagnosis of PAH remains challenging given its non-specific clinical symptomatology and the necessity for invasive hemodynamics assessment. As a result, PAH can be overlooked, which can delay diagnosis often until severe symptoms and RV failure present.1 Clinically, no reliable blood test is currently available to distinguish suspected PAH from PH secondary to left heart dysfunction (Group 2 PH) or hypoxia (Group 3 PH) and other cardiopulmonary conditions presenting with similar symptoms and to convince a clinician to pursue further invasive hemodynamic measurement. Furthermore, effective blood or plasma clinical biomarkers that correlate well with early pulmonary vasculature remodeling in PAH or with disease severity have been elusive to date.2
In a recent translational study, we analyzed the transcriptomic sequencing data from endothelial cells carrying BMPR2 mutations to identify unique genes that were differentially expressed relevant to BMPR2 deficiency.3 Among these genes, SCUBE1 contains a protein structure of both BMP1 and EGF domains and acts as a direct BMP co-receptor,4 making it a molecular candidate that mediates the BMPR2-relevant pulmonary endothelial functions. Indeed, in cultured pulmonary arterial endothelial cells, SCUBE1 was downregulated by multiple genetic or acquired pathogenic triggers of PAH, including BMPR2 deficiency induced by silencing RNA knockdown, hypoxia, or inflammatory factor exposure.
On the other hand, SCUBE1 deficiency induced by silencing RNA knockdown in pulmonary arterial endothelial cells recapitulated phenotypes associated with BMPR2 deficiency, including decreased angiogenic potential and increased apoptosis. SCUBE1 overexpression reversed the phenotypes associated with multiple known PAH triggers in vitro. These findings support a mechanistic model whereby SCUBE1 and BMPR2 form a positive feedback loop: the deficiency of either one of the two partners may transform the loop into a vicious cycle to further downregulate the overall BMPR2 functional status. Conversely, the enhancement of SCUBE1 or BMPR2 could result in augmented functional regulation due to positive feedback to each other. This hypothesis places SCUBE1 in a key position to maintain the BMPR2-relevant pulmonary endothelial function during initiation and/or development of PAH.
To translate these basic research findings into clinical applications, the diagnostic value of plasma levels of secreted SCUBE1 was examined in patients with PAH. SCUBE1 levels were significantly decreased in blood and tissue specimens collected from patients with PAH compared with those from multiple non-PAH cohorts, including healthy individuals and patients with PH secondary to left heart disease (Group 2 PH), chronic obstructive pulmonary disease, acute lung injuries or acute respiratory distress syndrome, and coronary artery disease. This specific decrease of SCUBE1 in blood from patients with PAH implies a potential to apply the plasma SCUBE1 measurement as a clinically applicable diagnostic biomarker for PAH. The receiver operating characteristic analysis between PAH and non-PAH cohorts suggests a high specificity of 0.87 and a sensitivity of 0.53 to distinguish PAH from the non-PAH cohorts, with an optimal plasma SCUBE1 cut point of 5.46 ng/mL. The receiver operating characteristic analysis between Group 1 PAH and Group 2 PH cohorts results in a specificity of 0.82 and a sensitivity of 0.50 to discriminate between these PH subtypes, at an optimal plasma SCUBE1 cut point of 5.01 ng/mL.
Further analysis suggested that the decrease of plasma SCUBE1 is correlated with the severity and progression of pulmonary vascular remodeling and RV function. In patients with PAH, plasma SCUBE1 levels were found to be progressively reduced with increasing levels of either mean pulmonary artery pressure or pulmonary vascular resistance. No correlation was observed between pulmonary capillary wedge pressure or cardiac output and plasma SCUBE1 levels. Plasma SCUBE1 levels were also significantly lower in patients with PAH with echocardiographic indices of severe PAH, including RV hypertrophy, moderate to severe RV dilation, or decreased tricuspid annular plane systolic excursion. The key regulatory effect of SCUBE1 on pulmonary endothelial functions provide a mechanistic explanation for the value of SCUBE1 as a biomarker for pulmonary vascular remodeling and dysfunction in PAH.
From a clinical standpoint, the significance of SCUBE1 in PAH diagnosis needs to be confirmed with large and external cohorts of patients. Clinical studies with prospective and increased enrollment have been planned for further validation and statistical analysis. It is also valuable to assess the diagnostic efficacy of plasma SCUBE1 measurements in PAH groups clinically stratified by sex, age, and PAH-associated etiological conditions. The correlation of plasma SCUBE1 with vasodilatory therapies and its predictive value for disease outcome and quality of life would also be interesting subjects for future studies.
- Brown LM, Chen H, Halpern S, et al. Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry. Chest 2011;140:19-26.
- Anwar A, Ruffenach G, Mahajan A, Eghbali M, Umar S. Novel biomarkers for pulmonary arterial hypertension. Respir Res 2016;17:88.
- Sun W, Tang Y, Tai YY, et al. SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension. JACC Basic Transl Sci 2020;5:1073-92.
- Tu CF, Yan YT, Wu SY, et al. Domain and functional analysis of a novel platelet-endothelial cell surface protein, SCUBE1. J Biol Chem 2008;283:12478-88.
Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Novel Agents, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Echocardiography/Ultrasound
Keywords: Hypertension, Pulmonary, Quality of Life, Epidermal Growth Factor, Pulmonary Wedge Pressure, Pulmonary Artery, Coronary Artery Disease, Endothelial Cells, ROC Curve, Transcriptome, Dilatation, Prospective Studies, Bone Morphogenetic Protein Receptors, Type II, Vascular Resistance, Pulmonary Disease, Chronic Obstructive, Cardiac Output, Echocardiography, Respiratory Distress Syndrome, Adult, Biological Markers, Phenotype, Hematologic Tests, Acute Lung Injury, Severity of Illness Index, Apoptosis, RNA
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