Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn

Kaluarachchi, Dinushan C.; Smith, Caitlin J.; Klein, Jonathan M.; Murray, Jeffrey C.; Dagle, John M.; Ryckman, Kelli K.

doi:10.1038/pr.2017.143

Cited by 25 publications

(25 citation statements)

References 34 publications

(37 reference statements)

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“…NO, a critical factor in cell growth and vasodilation has been well profiled in the pathogenesis of PAH [ 21 – 23 ]. The substrate of NO is arginine, which is mainly supplied by the urea cycle, is a linkage of the urea cycle to PAH [ 24 ]. NOS converts arginine to citrulline while simultaneously producing NO and water [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline

Zheng

Zhao

et al. 2018

Respir Res

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BackgroundPulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction. Although enormous metabolomic studies on PAH have been emerging, research remains lacking on metabolic reprogramming in experimental PAH models. We aim to evaluate the metabolic changes in PAH and provide new insight into endogenous metabolic disorders of PAH.MethodA single subcutaneous injection of monocrotaline (MCT) (60 mg kg− 1) was used for rats to establish PAH model. Hemodynamics and right ventricular hypertrophy were adopted to evaluate the successful establishment of PAH model. Plasma samples were assessed through targeted metabolomic profiling platform to quantify 126 endogenous metabolites. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to discriminate between MCT-treated model and control groups. Metabolite Set Enrichment Analysis was adapted to exploit the most disturbed metabolic pathways.ResultsEndogenous metabolites of MCT treated PAH model and control group were well profiled using this platform. A total of 13 plasma metabolites were significantly altered between the two groups. Metabolite Set Enrichment Analysis highlighted that a disruption in the urea cycle pathway may contribute to PAH onset. Moreover, five novel potential biomarkers in the urea cycle, adenosine monophosphate, urea, 4-hydroxy-proline, ornithine, N-acetylornithine, and two candidate biomarkers, namely, O-acetylcarnitine and betaine, were found to be highly correlated with PAH.ConclusionThe present study suggests a new role of urea cycle disruption in the pathogenesis of PAH. We also found five urea cycle related biomarkers and another two candidate biomarkers to facilitate early diagnosis of PAH in metabolomic profile.

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Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline

Zheng

Zhao

et al. 2018

Respir Res

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“… 33 NO is generated from L-arginine, supplied by the urea cycle. 34 Arginine is regulated by ASS1 and CPS1, and thus the loss of ASS1 and CPS1 might lead to reduction of NO. It is suggested that overexpression of NO in tumor tissues induces tumor cell toxicity and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Tandem Mass Tag-Based Proteomic Analysis of Potential Biomarkers for Hepatocellular Carcinoma Differentiation

Wang¹,

Li²,

Huang³

et al. 2021

OTT

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Purpose The poor prognosis of hepatocellular carcinoma (HCC) urgent us to discover early and effective biomarkers. In this study, we applied tandem mass tag (TMT)-based proteomic analysis to discover potential protein markers for HCC identification and differentiation. Patients and Methods Fifteen patients, well-differentiated (G1, N = 5), moderate-differentiated (G2, N = 5), and poorly differentiated (G3, N = 5), with 30 matched pair tissues (both tumor and adjacent non-tumor tissues derived from the same patient) were enrolled. All samples were subjected to TMT labeling and LC−MS/MS analysis. The identified proteins were subsequently assigned to GO and KEGG for predicting function. The identified protein candidates were validated using immunohistochemistry (IHC). Results A total of 1010 proteins were identified. Of these, 154 differentially expressed proteins (DEPs), 100 up-regulated and 54 down-regulated, were found between tumor and adjacent non-tumor tissues; 12 DEPs, 9 up-regulated and 3 down-regulated, were found between G1 and G3 tissues; 8 DEPs, 5 up-regulated and 3 down-regulated, were found between G1 and G2 tissues; 11 DEPs, 8 up-regulated and 3 down-regulated, were found between G2 and G3 tissues. Among them, ASS1 and CPS1 were significantly up-regulated while UROD and HBB were significantly down-regulated in G3 compared with G1 and G2 tumors. Three proteins, CYB5A, FKBP11 and YBX1, were significantly up-regulated in G1 compared with both G2 and G3 tumors. The 7 biomarker candidates were further verified by IHC. Conclusion A variety of DEPs related to the histological differentiation of HCC were identified, among which ASS1, CPS1, URPD and HBB proteins were potential biomarkers for distinguishing poorly differentiated HCC, while CYB5A, FKBP11 and YBX1 were potential biomarkers for distinguishing well-differentiated HCC. Our findings may further provide a new insight facilitating the diagnosis and prognosis of HCC.

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“…Additionally, we found three variants in CPS1 , one in a homozygous state, a gene for which neonatal susceptibility to PAH has been suggested with an increase of pulmonary arterial pressure after a surgical repair of congenital heart defects [ 37 ]. Furthermore, polymorphisms in CPS1 have also been related to persistent pulmonary hypertension of the newborn (PPHN) [ 38 ]. All variants were classified as VUS and unfortunately, no parental samples were available for segregation analysis.…”

Section: Discussionmentioning

confidence: 99%

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Tenorio

Hernández-González

Gallego

et al. 2020

Genes

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Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.

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Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn

Cited by 25 publications

References 34 publications

Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline

Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline

Tandem Mass Tag-Based Proteomic Analysis of Potential Biomarkers for Hepatocellular Carcinoma Differentiation

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

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