scholarly journals Investigating pulmonary arterial hypertension from “stem” to stern. Focus on “Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension”

2014 ◽  
Vol 307 (5) ◽  
pp. C413-C414 ◽  
Author(s):  
Katherine A. Cottrill ◽  
Stephen Y. Chan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cell Types ◽  
Genetic Signature ◽  
Multiple Cell ◽  
Pulmonary Arterial

scholarly journals Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

2014 ◽  
Vol 307 (5) ◽  
pp. C415-C430 ◽  
Author(s):  
James D. West ◽  
Eric D. Austin ◽  
Christa Gaskill ◽  
Shennea Marriott ◽  
Rubin Baskir ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Wnt Signaling Pathway ◽  
Cell Types ◽  
Patient Specific ◽  
Molecular Defect ◽  
Expression Array ◽  
Genetic Signature ◽  
Multiple Cell ◽  
Pulmonary Arterial

Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH.

scholarly journals Pulmonary arterial hypertension: Cellular and molecular changes in the lung

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Bradley A Maron
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Molecular Changes ◽  
Mesenchymal Transition ◽  
Disease Trajectory ◽  
Analytical Strategies ◽  
Multiple Cell ◽  
Pulmonary Arterial

The range of cell types identified in the pathogenesis of pulmonary arterial hypertension (PAH) has expanded substantially since the first pathological descriptions of this disease. This, inturn, has provided needed clarity on the gamut of molecular mechanisms that regulate vascular remodeling and promote characteristic cardiopulmonary hemodynamic changes that define PAH clinically. Insight derived from these scientific advances suggest that the PAH arteriopathy is due to the convergence of numerous molecular mechanisms driving cornerstone endophenotypes, such as plexigenic, hypertrophic, and fibrotic histopathological changes. Interestingly, whilesome endophenotypes are observed commonly in multiple cell types, such as dysregulated metabolism, other events such as endothelial-mesenchymal transition are cell type-specific. Integrating data from classical PAH vascular cell types with fresh information in pericytes, adventitial fibroblasts, and other PAH contributors recognized more recently has enriched the field with deeper understanding on the molecular basis of this disease. This added complexity, however, also serves as the basis for utilizing novel analytical strategies that emphasize functional signaling pathways when extracting information from big datasets. With these concepts as the backdrop, the current work offers a concise summary of cellular and molecular changes in the lung that drive PAH and may, thus, be important for discovering novel therapeutic targets or applications to clarify PAH onset and disease trajectory.

scholarly journals Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 170
Author(s):  
Linh Ho ◽  
Nazir Hossen ◽  
Trieu Nguyen ◽  
Au Vo ◽  
Fakhrul Ahsan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Right Heart Failure ◽  
Cell Types ◽  
Epigenetic Mechanisms ◽  
Microfluidic Chips ◽  
Transcriptional Responses ◽  
Pulmonary Arterial ◽  
Epigenetic Regulators

Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.

scholarly journals Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production

2021 ◽  
Vol 8 ◽  
Author(s):  
Ting Shu ◽  
Yanjiang Xing ◽  
Jing Wang
Keyword(s):  
Immune Response ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Connective Tissue Diseases ◽  
Cell Types ◽  
Specific Cell ◽  
Virus Infections ◽  
Immunoglobulin Production ◽  
Life Threatening ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease. The notion that autoimmunity is associated with PAH is widely recognized by the observations that patients with connective tissue diseases or virus infections are more susceptible to PAH. However, growing evidence supports that the patients with idiopathic PAH (IPAH) with no autoimmune diseases also have auto-antibodies. Anti-inflammatory therapy shows less help in decreasing auto-antibodies, therefore, elucidating the process of immunoglobulin production is in great need. Maladaptive immune response in lung tissues is considered implicating in the local auto-antibodies production in patients with IPAH. In this review, we will discuss the specific cell types involved in the lung in situ immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.

scholarly journals Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

2020 ◽  
Vol 9 (2) ◽  
pp. 561 ◽  
Author(s):  
Thomas Koudstaal ◽  
Karin A. Boomars ◽  
Mirjam Kool
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Immune Cells ◽  
Survival Rates ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Cell Types ◽  
Current Treatment ◽  
Adaptive Immune Cells ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

scholarly journals Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension

2020 ◽  
Vol 10 (1) ◽  
pp. ??? ◽  
Author(s):  
Didem Saygin ◽  
Tracy Tabib ◽  
Humberto E.T. Bittar ◽  
Eleanor Valenzi ◽  
John Sembrat ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cell Types ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Differential Gene ◽  
Pulmonary Arterial

Despite recent improvements in management of idiopathic pulmonary arterial hypertension, mortality remains high. Understanding the alterations in the transcriptome–phenotype of the key lung cells involved could provide insight into the drivers of pathogenesis. In this study, we examined differential gene expression of cell types implicated in idiopathic pulmonary arterial hypertension from lung explants of patients with idiopathic pulmonary arterial hypertension compared to control lungs. After tissue digestion, we analyzed all cells from three idiopathic pulmonary arterial hypertension and six control lungs using droplet-based single cell RNA-sequencing. After dimensional reduction by t-stochastic neighbor embedding, we compared the transcriptomes of endothelial cells, pericyte/smooth muscle cells, fibroblasts, and macrophage clusters, examining differential gene expression and pathways implicated by analysis of Gene Ontology Enrichment. We found that endothelial cells and pericyte/smooth muscle cells had the most differentially expressed gene profile compared to other cell types. Top differentially upregulated genes in endothelial cells included novel genes: ROBO4, APCDD1, NDST1, MMRN2, NOTCH4, and DOCK6, as well as previously reported genes: ENG, ORAI2, TFDP1, KDR, AMOTL2, PDGFB, FGFR1, EDN1, and NOTCH1. Several transcription factors were also found to be upregulated in idiopathic pulmonary arterial hypertension endothelial cells including SOX18, STRA13, LYL1, and ELK, which have known roles in regulating endothelial cell phenotype. In particular, SOX18 was implicated through bioinformatics analyses in regulating the idiopathic pulmonary arterial hypertension endothelial cell transcriptome. Furthermore, idiopathic pulmonary arterial hypertension endothelial cells upregulated expression of FAM60A and HDAC7, potentially affecting epigenetic changes in idiopathic pulmonary arterial hypertension endothelial cells. Pericyte/smooth muscle cells expressed genes implicated in regulation of cellular apoptosis and extracellular matrix organization, and several ligands for genes showing increased expression in endothelial cells. In conclusion, our study represents the first detailed look at the transcriptomic landscape across idiopathic pulmonary arterial hypertension lung cells and provides robust insight into alterations that occur in vivo in idiopathic pulmonary arterial hypertension lungs.

scholarly journals Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities

2017 ◽  
Vol 313 (6) ◽  
pp. R693-R705 ◽  
Author(s):  
Salema Jafri ◽  
Mark L. Ormiston
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Immune Cell ◽  
Small Animal ◽  
Cell Types ◽  
Systemic Hypertension ◽  
Defined Contribution ◽  
Hypertensive Disorders ◽  
Immune Mediated ◽  
Pulmonary Arterial

Systemic hypertension, preeclampsia, and pulmonary arterial hypertension (PAH) are diseases of high blood pressure in the systemic or pulmonary circulation. Beyond the well-defined contribution of more traditional pathophysiological mechanisms, such as changes in the renin–angiotensin–aldosterone system, to the development of these hypertensive disorders, there is substantial clinical evidence supporting an important role for inflammation and immunity in the pathogenesis of each of these three conditions. Over the last decade, work in small animal models, bearing targeted deficiencies in specific cytokines or immune cell subsets, has begun to clarify the immune-mediated mechanisms that drive changes in vascular structure and tone in hypertensive disease. By summarizing the clinical and experimental evidence supporting a contribution of the immune system to systemic hypertension, preeclampsia, and PAH, the current review highlights the cellular and molecular pathways that are common to all three hypertensive disorders. These mechanisms are centered on an imbalance in CD4+ helper T cell populations, defined by excessive Th17 responses and impaired Treg activity, as well as the excessive activation or impairment of additional immune cell types, including macrophages, dendritic cells, CD8+ T cells, B cells, and natural killer cells. The identification of common immune mechanisms in systemic hypertension, preeclampsia, and PAH raises the possibility of new therapeutic strategies that target the immune component of hypertension across multiple disorders.

scholarly journals Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension

2020 ◽  
Vol 55 (4) ◽  
pp. 1901761 ◽  
Author(s):  
Catherine E. Simpson ◽  
Jenny Y. Chen ◽  
Rachel L. Damico ◽  
Paul M. Hassoun ◽  
Lisa J. Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Severe Disease ◽  
Connective Tissue Diseases ◽  
Cell Types ◽  
Expression Levels ◽  
Clinical Phenotypes ◽  
Pulmonary Arterial ◽  
Gene Expression Levels

The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08–1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.

scholarly journals The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (9) ◽  
pp. 3305
Author(s):  
Ari Simenauer ◽  
Eva Nozik-Grayck ◽  
Adela Cota-Gomez
Keyword(s):  
Dna Damage ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dna Damage Response ◽  
Regulatory Networks ◽  
Cell Types ◽  
Pulmonary Vasculature ◽  
Increased Risk ◽  
Damage Response ◽  
Pulmonary Arterial

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

scholarly journals Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
pp. 204589402199619
Author(s):  
Sharon Mumby ◽  
F. Perros ◽  
C. Hui ◽  
B.L. Xu ◽  
W. Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cell Types ◽  
Microvascular Endothelial Cells ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Human Pulmonary Artery

Pulmonary arterial hypertension describes a group of diseases characterised by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between pulmonary arterial hypertension and controls using both human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells. Human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalisation, we examined differentially expressed genes and applied gene set enrichment analysis to the differentially expressed genes to identify putative activated pathways. Human pulmonary microvascular endothelial cells displayed 1008 significant ( p ≤ 0.0001) differentially expressed genes in pulmonary arterial hypertension samples compared to controls. In human pulmonary artery smooth muscle cells, there were 229 significant ( p ≤ 0.0001) differentially expressed genes between pulmonary arterial hypertension and controls. Pathway analysis revealed distinctive differences: human pulmonary microvascular endothelial cells display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell-adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in pulmonary arterial hypertension pathogenesis. In contrast, pathways in human pulmonary artery smooth muscle cells were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell–cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in pulmonary arterial hypertension pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.

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