Potential biomarkers and targets in reversibility of pulmonary arterial hypertension secondary to congenital heart disease: an explorative study

Huang, Li; Li, Li; Hu, Enci; Guo, Chen; Meng, Xia; Xiong, Changming; He, Jian‐Guo

doi:10.1177/2045893218755987

Cited by 22 publications

(30 citation statements)

References 28 publications

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“…To explore the pathogenetic mechanism of irreversible CHD‐PAH, proteomics comparison of the lung tissues in both reversible and irreversible CHD‐PAH patients as well as in normal were performed. Proteomic analysis showed that transgelin was significantly up‐regulated (2.5‐fold) in irreversible CHD‐PAH group compared to the reversible and control group . Immunohistochemical staining and Western blot also confirmed the findings, and the expression of transgelin was significantly positively related with pathological grading of pulmonary arterioles.…”

Section: Introductionsupporting

confidence: 59%

Transgelin as a potential target in the reversibility of pulmonary arterial hypertension secondary to congenital heart disease

Huang

Yang

et al. 2018

J Cellular Molecular Medi

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BackgroundThe reversibility of pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) is of great importance for the operability of CHD. Proteomics analysis found that transgelin was significantly up‐regulated in the lung tissue of CHD‐PAH patients, especially in the irreversible group. However, how exactly it participated in CHD‐PAH development is unknown.MethodsImmunohistochemical staining and Western blot were performed for further qualitative and quantitative analysis of transgelin in the lung tissues of CHD‐PAH patients. The mechanism of transgelin in CHD‐PAH development was explored in vitro. Primary human pulmonary arterial smooth muscle cells (hPASMCs) were cultured and infected with TAGLN siRNA or TAGLN lentiviral vector. Cell morphologic change (Coomassie Brilliant Blue staining), proliferation (cell count and EdU assay), apoptosis (terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling assay and Annexin‐V flow cytometry) and migration (transwell) were evaluated following the cell treatment. The mRNA and protein expression levels were detected in real‐time PCR and Western blot.ResultsIn line with the proteomic findings, transgelin was obviously expressed in PASMC of the middle pulmonary arterioles, especially in the irreversible PAH group. Also, transgelin expression showed positive relation with pathological grading. Experiment in vitro demonstrated that transgelin overexpression promoted PASMC proliferation and migration, strengthened cytoskeleton and was accompanied by increased expression of synthetic phenotype markers (osteopontin, proliferating cell nuclear antigen) and anti‐apoptotic protein (bcl‐2). On the other hand, suppression of transgelin expression activated PASMC apoptosis, reducing cell proliferation and migration.ConclusionsTransgelin may be a potential target in the development of irreversible CHD‐PAH through inducing PASMC phenotype change, proliferation, migration and reducing cell apoptosis.

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Section: Introductionsupporting

confidence: 59%

Transgelin as a potential target in the reversibility of pulmonary arterial hypertension secondary to congenital heart disease

Huang

Yang

et al. 2018

J Cellular Molecular Medi

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“…Seemingly contradictory, caveolin-1 is known to amplify beneficial BMPR2 signalling in ECs,42 and mutations or loss of caveolin-1 in ECs are generally associated with the development of PAH. However, caveolin-1 expression was indeed found to increase with disease progression in the media of remodelled arteries in end-stage IPAH and PAH-CHD 41. This temporal expression pattern makes caveolin-1 a potential marker to distinguish reversibility.…”

Section: Structural Functional and Molecular Assessment Of The Pulmomentioning

confidence: 94%

“…A recent study compared the metabolomics blood profiles of 10 early, reversible and four patients with advanced, irreversible PAH using mass spectrometry 41. In this small cohort, four candidate proteins were found with discriminative potential between groups: caveolin-1, filamin-1A, cathepsin-D (increased in irreversible PAH) and glutathione S-transferase mu1 (GSTM1; decreased in irreversible PAH).…”

Section: Structural Functional and Molecular Assessment Of The Pulmomentioning

confidence: 99%

“…Filamin-1A is associated with apoptosis-resistance, and cathepsin-D to elastin and collagen degradation, and to vascular remodelling: processes all consistent with end-stage PAH pathology. GSTM1 finally is associated with protection against reactive oxygen species (ROS) 41. ROS induces DNA damages which propagates the progression of PAH 43.…”

Section: Structural Functional and Molecular Assessment Of The Pulmomentioning

confidence: 99%

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Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease

Feen

Bartelds

Boer³

et al. 2018

Heart

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Pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) can be reversed by early shunt closure, but this potential is lost beyond a certain point of no return. Therefore, it is crucial to accurately assess the reversibility of this progressive pulmonary arteriopathy in an early stage. Reversibility assessment is currently based on a combination of clinical symptoms and haemodynamic variables such as pulmonary vascular resistance. These measures, however, are of limited predictive value and leave many patients in the grey zone. This review provides a concise overview of the mechanisms involved in flow-dependent progression of PAH in CHD and evaluates existing and future alternatives to more directly investigate the stage of the pulmonary arteriopathy. Structural quantification of the pulmonary arterial tree using fractal branching algorithms, functional imaging with intravascular ultrasound, nuclear imaging, putative new blood biomarkers, genetic testing and the potential for transcriptomic analysis of circulating endothelial cells and educated platelets are being reviewed.

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“…14 Huang et al proposed some pathological biomarkers. 15 In irreversible PAH, they found increased expression of caveolin-1, filaminA, and cathepsin D and decreased glutathione S-transferase mu 1 (GSTM1) from a lung biopsy, which could be used as an expression profile to predict irreversible PAH caused by CHD. 15 Hopefully, new and improved methods to evaluate the histological findings, and the discovery of new biomarkers will lead to better understanding of the pathogenesis of PAH in patients with DS.…”

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confidence: 99%

What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease?

Hosokawa

Vanderpool

Ishii

et al. 2018

Circ J

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H-E classification and IPVD score. Furthermore, earlier progression of histopathological changes in pulmonary arteriopathy could not be proved in patients with DS despite accounting for age in the histological findings. Previous papers have reported no difference in the incidence of PAH between patients with DS and those without DS. Vázquez-Antona et al showed that results of a hemodynamic study of pulmonary hypertension and vasodilation test with oxygen were similar for patients with DS and those without the chromosomal abnormality, 10 though they did not examine histological findings.Cohort selection, other types of respiratory problems and anatomic variability are other reasons that could explain the results in the current study by Masaki et al. Patients who had undergone pulmonary artery banding were excluded from this study, which might cause underestimation of the severity of pulmonary arteriopathy in the group of patients with DS. Other factors could be contributing to the pathogenesis of PAH in patients with DS. Pandit et al suggest there are many respiratory problems in both the upper and lower airways of children with DS. 11 Anatomic characteristics in DS such as large tongue, small hypopharynx, pharyngeal hypotonia, tonsils and adenoid enlargement, laryngomalacia, and tracheomalacia cause upper airway problems. In addition, gastroesophageal reflux, immunologic dysfunction, tracheal bronchus, airway malacia, CHD, and pulmonary hypoplasia cause recurrent lower airway diseases. 11 Cooney and Thurlbeck showed that 6 of 7 patients with DS had hypoplastic lungs, and 5 had CHD. 12 Patients with DS have a decreased number of alveoli in relation to acini, enlarged alveoli and alveolar ducts, and a smaller alveolar surface area, which can lead to exacerbation of pulmonary hypertension in DS. 12 Bush et al investigated the histologic features of impaired development of the lung vasculature and alveoli and the presence of intrapulmonary bronchopulmonary anastomoses (IBA) in patients with DS using specimens obtained from autopsy. 13 These patients had frequent histologic evidence of impaired lung alveolar and vascular development, D own syndrome (DS) is the most common chromosomal abnormality. A recent study showed that its incidence is 1 in 319-1,000 live births. 1 Approximately half of all newborns with DS have congenital heart disease (CHD): 2 atrioventricular septal defect (AVSD: 45%), ventricular septal defect (VSD: 35%), secundum atrial septal defect (8%), and tetralogy of Fallot (4%). 3 DS strongly associates with pulmonary arterial hypertension (PAH). Patients with DS and CHD are thought to develop PAH more rapidly than non-DS patients with CHD. 4 In patients with DS and severe pulmonary hypertension, cardiologists need to determine whether there are surgical indications when they perform the cardiac catheterizations. In those cases, the Heath-Edwards (H-E) classification, and in Japan the index of pulmonary vascular disease (IPVD) 5 proposed by Yamaki and Tezuka, 6 determined from a lung biopsy play an im...

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Potential biomarkers and targets in reversibility of pulmonary arterial hypertension secondary to congenital heart disease: an explorative study

Cited by 22 publications

References 28 publications

Transgelin as a potential target in the reversibility of pulmonary arterial hypertension secondary to congenital heart disease

Transgelin as a potential target in the reversibility of pulmonary arterial hypertension secondary to congenital heart disease

Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease

What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease?

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