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.

Myocardial adaptation and exercise performance in patients with pulmonary arterial hypertension assessed with patient-specific computer simulations

2021 ◽  
Vol 321 (5) ◽  
pp. H865-H880
Author(s):  
Niels Thue Olsen ◽  
Christoffer Göransson ◽  
Niels Vejlstrup ◽  
Jørn Carlsen
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Computer Simulations ◽  
Patient Specific ◽  
Limiting Factor ◽  
Myocardial Mechanics ◽  
Use Of Data ◽  
Pulmonary Arterial ◽  
Myocardial Adaptation ◽  
Rest And Exercise

Computer simulations of the myocardial mechanics and hemodynamics of rest and exercise were performed in nine patients with pulmonary arterial hypertension and 10 control subjects, with the use of data from invasive catheterization and from cardiac magnetic resonance. This approach allowed a detailed analysis of myocardial adaptation to pulmonary arterial hypertension and showed how reduction in right ventricular inotropic reserve is the important limiting factor for an increase in cardiac output during exercise.

scholarly journals Patient-Specific Computational Analysis of Ventricular Mechanics in Pulmonary Arterial Hypertension

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Ce Xi ◽  
Candace Latnie ◽  
Xiaodan Zhao ◽  
Ju Le Tan ◽  
Samuel T. Wall ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Left Ventricle ◽  
Arterial Hypertension ◽  
Pressure Gradient ◽  
Circumferential Strain ◽  
Patient Specific ◽  
Free Wall ◽  
Mr Images ◽  
Ventricular Mechanics ◽  
Pulmonary Arterial

Patient-specific biventricular computational models associated with a normal subject and a pulmonary arterial hypertension (PAH) patient were developed to investigate the disease effects on ventricular mechanics. These models were developed using geometry reconstructed from magnetic resonance (MR) images, and constitutive descriptors of passive and active mechanics in cardiac tissues. Model parameter values associated with ventricular mechanical properties and myofiber architecture were obtained by fitting the models with measured pressure–volume loops and circumferential strain calculated from MR images using a hyperelastic warping method. Results show that the peak right ventricle (RV) pressure was substantially higher in the PAH patient (65 mmHg versus 20 mmHg), who also has a significantly reduced ejection fraction (EF) in both ventricles (left ventricle (LV): 39% versus 66% and RV: 18% versus 64%). Peak systolic circumferential strain was comparatively lower in both the left ventricle (LV) and RV free wall (RVFW) of the PAH patient (LV: −6.8% versus −13.2% and RVFW: −2.1% versus −9.4%). Passive stiffness, contractility, and myofiber stress in the PAH patient were all found to be substantially increased in both ventricles, whereas septum wall in the PAH patient possessed a smaller curvature than that in the LV free wall. Simulations using the PAH model revealed an approximately linear relationship between the septum curvature and the transseptal pressure gradient at both early-diastole and end-systole. These findings suggest that PAH can induce LV remodeling, and septum curvature measurements may be useful in quantifying transseptal pressure gradient in PAH patients.

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.

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