Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension

He, Yangyang; Yi, Yan; Jiang, Xin; Zhao, Jiying; Wang, Zhe; Wu, Tao Cheng; Wang, Yong; Guo, Shanshan; Ye, Jue; Lian, Tian‐Yu; Xu, Xiequn; Zhang, Jinlan; Sun, Kai; Peng, Fuhua; Zhou, Yu‐Ping; Mao, Yimin; Zhang, Xue; Chen, Jiwang; Zhang, Shuyang; Jing, Zhi‐Cheng

doi:10.1183/13993003.00522-2020

Cited by 43 publications

(35 citation statements)

References 53 publications

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“…ATP13A3 encodes a transmembrane cation transporter, which was recently shown to transport polyamines 8. Polyamines are small metabolites required for normal cell growth and proliferation, and elevated concentrations have been reported in multiple cancers and, more recently, PAH 20 21 . ATP13A3 is widely expressed in developing embryo and adult tissues,22 including pulmonary arterial smooth muscle cells (PASMC) 3.…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

et al. 2021

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BackgroundThe molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and resultsWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent–offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.ConclusionOur findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

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Section: Discussionmentioning

confidence: 99%

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

et al. 2021

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“…In adults, polyamines are also associated with cardiovascular disease. For example, excess spermine exacerbates abnormal vascular remodeling, which is involved in pulmonary arterial hypertension, and spermine regulation by SMS inhibition is a potential therapeutic method (He et al, 2020). In addition, spermidine, another polyamine, improves age‐related vascular disorders such as arteriosclerosis (J. Wang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing of 45 Japanese patients with intellectual disability

Abe-Hatano

Iida

Kosugi

et al. 2021

American J of Med Genetics Pt A

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Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single‐step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.

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“…Circulating indoleamine 2,3-dioxygenase-dependent tryptophan metabolites, tricarboxylic acid intermediates, purine metabolites and arginine-nitric oxide metabolites were revealed to be associated with hemodynamic indicators of right ventricular-pulmonary vascular function by targeted mass spectrometry (Lewis et al, 2016). Our previous study also showed higher plasma levels of spermine in two independent cohorts of idiopathic PAH patients by targeted metabolomic strategy and inhibition of spermine synthesis could inhibit PASMC proliferation in vitro and retard PH progression in vivo (He et al, 2020). All the findings implicate the disrupted metabolites could serve as potential biomarkers in PH and the correction of metabolism disturbance via modulation of related metabolism associated genes (eg.…”

Section: Discussionmentioning

confidence: 83%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Front. Pharmacol.

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Objective: Pulmonary hypertension (PH) associated with hypoxia and lung disease (Group 3) is the second most common form of PH and associated with increased morbidity and mortality. This study was aimed to identify hypoxia induced metabolism associated genes (MAGs) for better understanding of hypoxic PH.Methods: Rat pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured in normoxic or hypoxic condition for 24 h. Cells were harvested for liquid chromatography-mass spectrometry analysis. Functional annotation of distinguishing metabolites was performed using Metaboanalyst. Top 10 enriched metabolite sets were selected for the identification of metabolism associated genes (MAGs) with a relevance score >8 in Genecards. Transcriptomic data from lungs of hypoxic PH in mice/rats or of PH patients were accessed from Gene Expression Omnibus (GEO) database or open-access online platform. Connectivity Map analysis was performed to identify potential compounds to reverse the metabolism associated gene profile under hypoxia stress. The construction and module analysis of the protein-protein interaction (PPI) network was performed. Hub genes were then identified and used to generate LASSO model to determine its accuracy to predict occurrence of PH.Results: A total of 36 altered metabolites and 1,259 unique MAGs were identified in rat PASMCs under hypoxia. 38 differentially expressed MAGs in mouse lungs of hypoxic PH were revealed, with enrichment in multi-pathways including regulation of glucose metabolic process, which might be reversed by drugs such as blebbistatin. 5 differentially expressed MAGs were displayed in SMCs of Sugen 5416/hypoxia induced PH rats at the single cell resolution. Furthermore, 6 hub genes (Cat, Ephx1, Gpx3, Gstm4, Gstm5, and Gsto1) out of 42 unique hypoxia induced MAGs were identified. Higher Cat, Ephx1 and lower Gsto1 were displayed in mouse lungs under hypoxia (all p < 0.05), in consistent with the alteration in lungs of PH patients. The hub gene-based LASSO model can predict the occurrence of PH (AUC = 0.90).Conclusion: Our findings revealed six hypoxia-induced metabolism associated hub genes, and shed some light on the molecular mechanism and therapeutic targets in hypoxic PH.

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Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension

Cited by 43 publications

References 53 publications

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

Whole genome sequencing of 45 Japanese patients with intellectual disability

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

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