Gene expression profiling of common signal transduction pathways affected by rBMSCs/F92A-Cav1 in the lungs of rat with pulmonary arterial hypertension

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

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Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽

10.3390/biom11101475 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1475

Author(s):

Veronica Ruta ◽

Vittoria Pagliarini ◽

Claudio Sette

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Rna Processing ◽

Translational Regulation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Signal Transduction Pathways ◽

Challenges And Opportunities ◽

Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

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Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00106.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. L483-L491 ◽

Cited By ~ 28

Author(s):

Mirjam E. van Albada ◽

Beatrijs Bartelds ◽

Hans Wijnberg ◽

Saffloer Mohaupt ◽

Michael G. Dickinson ◽

...

Keyword(s):

Gene Expression ◽

Blood Flow ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Blood Flow ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Response To Therapy ◽

High Morbidity ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.

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Gene Expression Profiling of Grass Carp (Ctenopharyngodon idellus) and Crisp Grass Carp

International Journal of Genomics ◽

10.1155/2014/639687 ◽

2014 ◽

Vol 2014 ◽

pp. 1-15 ◽

Cited By ~ 8

Author(s):

Ermeng Yu ◽

Jun Xie ◽

Guangjun Wang ◽

Deguang Yu ◽

Wangbao Gong ◽

...

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Grass Carp ◽

Expression Profiling ◽

Calcium Metabolism ◽

Value Added ◽

Signal Transduction Pathways ◽

Ctenopharyngodon Idellus ◽

Biological Functions ◽

Number Of Genes

Grass carp (Ctenopharyngodon idellus) is one of the most important freshwater fish that is native to China, and crisp grass carp is a kind of high value-added fishes which have higher muscle firmness. To investigate biological functions and possible signal transduction pathways that address muscle firmness increase of crisp grass carp, microarray analysis of 14,900 transcripts was performed. Compared with grass carp, 127 genes were upregulated and 114 genes were downregulated in crisp grass carp. Gene ontology (GO) analysis revealed 30 GOs of differentially expressed genes in crisp grass carp. And strong correlation with muscle firmness increase of crisp grass carp was found for these genes from differentiation of muscle fibers and deposition of ECM, and also glycolysis/gluconeogenesis pathway and calcium metabolism may contribute to muscle firmness increase. In addition, a number of genes with unknown functions may be related to muscle firmness, and these genes are still further explored. Overall, these results had been demonstrated to play important roles in clarifying the molecular mechanism of muscle firmness increase in crisp grass carp.

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ALDH1A3 Coordinates Metabolism with Gene Regulation in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circulationaha.120.048845 ◽

2021 ◽

Author(s):

Dan Li ◽

Ning-Yi Shao ◽

Jan-Renier Moonen ◽

Zhixin Zhao ◽

Minyi Shi ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cell Function ◽

Chromatin Modification ◽

Major Pathway ◽

Energy Needs ◽

Dividing Cells ◽

Pulmonary Arterial

Background: Metabolic alterations provide substrates that influence chromatin structure to regulate gene expression that determines cell function in health and disease. Heightened proliferation of smooth muscle cells (SMC) leading to the formation of a neointima is a feature of pulmonary arterial hypertension (PAH) and systemic vascular disease. Increased glycolysis is linked to the proliferative phenotype of these SMC. Methods: RNA Sequencing was applied to pulmonary arterial (PA) SMC from PAH patients with and without a BMPR2 mutation vs. control PASMC to uncover genes required for their heightened proliferation and glycolytic metabolism. Assessment of differentially expressed genes established metabolism as a major pathway, and the most highly upregulated metabolic gene in PAH PASMC was aldehyde dehydrogenase family 1 member 3 ( ALDH1A3 ), an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular SMC. We determined if these functions are ALDH1A3-dependent in PAH PASMC, and if ALDH1A3 is required for the development of pulmonary hypertension in a transgenic mouse. Nuclear localization of ALDH1A3 in PAH PASMC led us to determine whether and how this enzyme coordinately regulates gene expression and metabolism in PAH PASMC. Results: ALDH1A3 mRNA and protein were increased in PAH vs control PASMC, and ALDH1A3 was required for their highly proliferative and glycolytic properties. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced PA muscularization or pulmonary hypertension. Nuclear ALDH1A3 converted acetaldehyde to acetate to produce acetyl-CoA to acetylate H3K27, marking active enhancers. This allowed for chromatin modification at nuclear factor Y (NFY)A binding sites via the acetyltransferase KAT2B and permitted NFY mediated transcription of cell cycle and metabolic genes that is required for ALDH1A3-dependent proliferation and glycolysis. Loss of BMPR2 in PAH SMC with or without a mutation upregulated ALDH1A3, and transcription of NFYA and ALDH1A3 in PAH PASMC was β-catenin dependent. Conclusions: Our studies have uncovered a metabolic-transcriptional axis explaining how dividing cells use ALDH1A3 to coordinate their energy needs with the epigenetic and transcriptional regulation of genes required for SMC proliferation. They suggest that selectively disrupting the pivotal role of ALDH1A3 in PAH SMC, but not EC, is an important therapeutic consideration.

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BMPR2 Promoter Variants Effect Gene Expression in Pulmonary Arterial Hypertension Patients

Genes ◽

10.3390/genes11101168 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1168

Author(s):

Jie Song ◽

Katrin Hinderhofer ◽

Lilian T. Kaufmann ◽

Nicola Benjamin ◽

Christine Fischer ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Transcriptional Activity ◽

Disease Manifestation ◽

Pathogenic Variants ◽

Protein Receptor ◽

Transcriptional Effect ◽

Pulmonary Arterial ◽

Human Pulmonary Artery

Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 (BMPR2) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC, c.-930_-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation.

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Global Microrna Expression Profiling of Blood Outgrowth Endothelial Cells From Patients With Heritable Pulmonary Arterial Hypertension

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2013.07.270 ◽

2013 ◽

Vol 29 (10) ◽

pp. S175

Author(s):

K Schlosser ◽

ML Ormiston ◽

NW Morrell ◽

DJ Stewart

Keyword(s):

Endothelial Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Expression Profiling ◽

Microrna Expression ◽

Pulmonary Arterial ◽

Heritable Pulmonary Arterial Hypertension

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Identification of biomarkers and pathways for the SARS-CoV-2 infections that make complexities in pulmonary arterial hypertension patients

Briefings in Bioinformatics ◽

10.1093/bib/bbab026 ◽

2021 ◽

Author(s):

Tasnimul Alam Taz ◽

Kawsar Ahmed ◽

Bikash Kumar Paul ◽

Fahad Ahmed Al-Zahrani ◽

S M Hasan Mahmud ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Arterial Hypertension ◽

Epithelial Cells ◽

Arterial Hypertension ◽

Human Lung ◽

Genomic Analysis ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Pulmonary Arterial ◽

Human Lung Epithelial Cells

Abstract This study aimed to identify significant gene expression profiles of the human lung epithelial cells caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We performed a comparative genomic analysis to show genomic observations between SARS-CoV and SARS-CoV-2. A phylogenetic tree has been carried for genomic analysis that confirmed the genomic variance between SARS-CoV and SARS-CoV-2. Transcriptomic analyses have been performed for SARS-CoV-2 infection responses and pulmonary arterial hypertension (PAH) patients’ lungs as a number of patients have been identified who faced PAH after being diagnosed with coronavirus disease 2019 (COVID-19). Gene expression profiling showed significant expression levels for SARS-CoV-2 infection responses to human lung epithelial cells and PAH lungs as well. Differentially expressed genes identification and integration showed concordant genes (SAA2, S100A9, S100A8, SAA1, S100A12 and EDN1) for both SARS-CoV-2 and PAH samples, including S100A9 and S100A8 genes that showed significant interaction in the protein–protein interactions network. Extensive analyses of gene ontology and signaling pathways identification provided evidence of inflammatory responses regarding SARS-CoV-2 infections. The altered signaling and ontology pathways that have emerged from this research may influence the development of effective drugs, especially for the people with preexisting conditions. Identification of regulatory biomolecules revealed the presence of active promoter gene of SARS-CoV-2 in Transferrin-micro Ribonucleic acid (TF-miRNA) co-regulatory network. Predictive drug analyses provided concordant drug compounds that are associated with SARS-CoV-2 infection responses and PAH lung samples, and these compounds showed significant immune response against the RNA viruses like SARS-CoV-2, which is beneficial in therapeutic development in the COVID-19 pandemic.

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