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An evidence-based knowledgebase of pulmonary arterial hypertension to identify genes and pathways relevant to pathogenesis.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a major progressive form of pulmonary hypertension (PH) with more than 4800 patients in the United States. In the last two decades, many studies have identified numerous genes associated with this disease. However, there is no comprehensive research resource for PAH or other PH types that integrates various genetic studies and their related biological information. Thus, the number of associated genes, and their strength of evidence, is unclear. In this study, we tested the hypothesis that a web-based knowledgebase could be used to develop a biological map of highly interrelated, functionally important genes in PAH. We developed the pulmonary arterial hypertension knowledgebase (PAHKB, ), a comprehensive database with a user-friendly web interface. PAHKB extracts genetic data from all available sources, including those from association studies, genetic mutation, gene expression, animal model, supporting literature, various genomic annotations, gene networks, cellular and regulatory pathways, as well as microRNAs. Moreover, PAHKB provides online tools for data browsing and searching, data integration, pathway graphical presentation, and gene ranking. In the current release, PAHKB contains 341 human PH-related genes (293 protein coding and 48 non-coding genes) curated from over 1000 PubMed abstracts. Based on the top 39 ranked PAH-related genes in PAHKB, we constructed a core biological map. This core map was enriched with the TGF-beta signaling pathway, focal adhesion, cytokine-cytokine receptor interaction, and MAPK signaling. In addition, the reconstructed map elucidates several novel cancer signaling pathways, which may provide clues to support the application of anti-cancer therapeutics to PAH. In summary, we have developed a system for the identification of core PH-related genes and identified critical signaling pathways that may be relevant to PAH pathogenesis. This system can be easily applied to other pulmonary diseases.

SUBMITTER: Zhao M

PROVIDER: S-EPMC3950334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.

Project description:Background: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease. Owing to its high fatality rate and narrow therapeutic options, identification of the pathogenic mechanisms of IPAH is becoming increasingly important. Methods: In our research, we utilized the robust rank aggregation (RRA) method to integrate four eligible pulmonary arterial hypertension (PAH) microarray datasets and identified the significant differentially expressed genes (DEGs) between IPAH and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to analyze their functions. The interaction network of protein-protein interaction (PPI) was constructed to explore the correlation between these DEGs. The functional modules and hub genes were further identified by the weighted gene coexpression network analysis (WGCNA). Moreover, a miRNA microarray dataset was involved and analyzed to filter differentially expressed miRNAs (DE-miRNAs). Potential target genes of screened DE-miRNAs were predicted and merged with DEGs to explore a miRNA-mRNA network in IPAH. Some hub genes were selected and validated by RT-PCR in lung tissues from the PAH animal model. Results: A total of 260 DEGs, consisting of 183 upregulated and 77 downregulated significant DEGs, were identified, and some of those genes were novel. Their molecular roles in the etiology of IPAH remained vague. The most crucial functional module involved in IPAH is mainly enriched in biological processes, including leukocyte migration, cell chemotaxis, and myeloid leukocyte migration. Construction and analysis of the PPI network showed that CXCL10, CXCL9, CCR1, CX3CR1, CX3CL1, CXCR2, CXCR1, PF4, CCL4L1, and ADORA3 were recognized as top 10 hub genes with high connectivity degrees. WGCNA further identified five main functional modules involved in the pathogenesis of IPAH. Twelve upregulated DE-miRNAs and nine downregulated DE-miRNAs were identified. Among them, four downregulated DEGs and eight upregulated DEGs were supposed to be negatively regulated by three upregulated DE-miRNAs and three downregulated DE-miRNAs, respectively. Conclusions: This study identifies some key and functional coexpression modules involved in IPAH, as well as a potential IPAH-related miRNA-mRNA regulated network. It provides deepening insights into the molecular mechanisms and provides vital clues in seeking novel therapeutic targets for IPAH.

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An evidence-based knowledgebase of pulmonary arterial hypertension to identify genes and pathways relevant to pathogenesis.

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