scholarly journals Epigenetic Regulation of Endothelial Dysfunction and Inflammation in Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (22) ◽  
pp. 12098
Author(s):  
Jaylen Hudson ◽  
Laszlo Farkas
Keyword(s):  
Endothelial Dysfunction ◽  
Pulmonary Artery Hypertension ◽  
Metabolic Reprogramming ◽  
Pulmonary Vascular Disease ◽  
Epigenetic Changes ◽  
Apoptosis Resistance ◽  
Cell Dysfunction ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Once perceived as a disorder treated by vasodilation, pulmonary artery hypertension (PAH) has emerged as a pulmonary vascular disease with severe endothelial cell dysfunction. In the absence of a cure, many studies seek to understand the detailed mechanisms of EC regulation to potentially create more therapeutic options for PAH. Endothelial dysfunction is characterized by complex phenotypic changes including unchecked proliferation, apoptosis-resistance, enhanced inflammatory signaling and metabolic reprogramming. Recent studies have highlighted the role of epigenetic modifications leading to pro-inflammatory response pathways, endothelial dysfunction, and the progression of PAH. This review summarizes the existing literature on epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, which can lead to aberrant endothelial function. Our goal is to develop a conceptual framework for immune dysregulation and epigenetic changes in endothelial cells in the context of PAH. These studies as well as others may lead to advances in therapeutics to treat this devastating disease.

scholarly journals Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs

2020 ◽  
Vol 116 (12) ◽  
pp. 1937-1947 ◽  
Author(s):  
Kashif Rafiq Zahid ◽  
Umar Raza ◽  
Jidong Chen ◽  
Usha J Raj ◽  
Deming Gou
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular Dysfunction ◽  
Pulmonary Artery Hypertension ◽  
Endothelial Cell Proliferation ◽  
Vascular Remodelling ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Abstract Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.

scholarly journals Genetic and Epigenetic Aspects of Atopic Dermatitis

2020 ◽  
Vol 21 (18) ◽  
pp. 6484 ◽  
Author(s):  
Bogusław Nedoszytko ◽  
Edyta Reszka ◽  
Danuta Gutowska-Owsiak ◽  
Magdalena Trzeciak ◽  
Magdalena Lange ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Treatment Strategies ◽  
Structural Proteins ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Adaptive Immune ◽  
Genes Encoding ◽  
Inflammatory Processes ◽  
Non Coding Rnas

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

Sex Differences in Right Ventricular-Vascular Coupling and Pulmonary Artery Impedance in Response to Chronic Hypoxia and Recovery

2012 ◽  
Author(s):  
Aiping Liu ◽  
Lian Tian ◽  
Diana M. Tabima ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Pulmonary Artery Hypertension ◽  
Vascular Impedance ◽  
Female Predominance ◽  
Collagen Accumulation ◽  
Dominant Disease ◽  
Pulmonary Arterial

Pulmonary artery hypertension (PAH) is a female dominant disease (the female-to-male ratio is 4:1), characterized by small distal pulmonary arterial narrowing and large proximal arterial stiffening, which increase right ventricle (RV) afterload and ultimately lead to RV failure [1,2]. Our recent studies have shown that collagen accumulation induced by chronic hypoxia increases the stiffness of the large extralobar pulmonary arteries (PAs) [3], and affects pulmonary vascular impedance (PVZ) [4]. The role of collagen in the female predominance in developing PAH has not been explored to date.

Endothelial dysfunction and cardiometabolic diseases: Role of long non-coding RNAs

Life Sciences ◽  
2016 ◽  
Vol 167 ◽  
pp. 6-11 ◽  
Author(s):  
Hai-Jian Sun ◽  
Bao Hou ◽  
Xu Wang ◽  
Xue-Xue Zhu ◽  
Ke-Xue Li ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cardiometabolic Diseases ◽  
Non Coding Rnas

scholarly journals Emerging role of long non-coding RNAs in endothelial dysfunction and their molecular mechanisms

2022 ◽  
Vol 145 ◽  
pp. 112421
Author(s):  
Ravichandran Jayasuriya ◽  
Kumar Ganesan ◽  
Baojun Xu ◽  
Kunka Mohanram Ramkumar
Keyword(s):  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Non Coding Rnas

scholarly journals Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment

2021 ◽  
Vol 20 ◽  
pp. 153303382110378
Author(s):  
Qian Zhang ◽  
Xiangling Yang ◽  
Huanliang Liu
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Diagnosis ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Bioactive Molecules ◽  
Diagnosis And Treatment ◽  
Existing Problems ◽  
Non Coding Rnas

Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.

scholarly journals The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers

2021 ◽  
Vol 22 (16) ◽  
pp. 8527
Author(s):  
Leila Jahangiri ◽  
Perla Pucci ◽  
Tala Ishola ◽  
Ricky M. Trigg ◽  
John A. Williams ◽  
...  
Keyword(s):  
Gene Networks ◽  
Regulatory Networks ◽  
Metabolic Reprogramming ◽  
Cellular Processes ◽  
Cancer Genomes ◽  
Mutual Regulation ◽  
Myc Gene ◽  
Gene Regulatory ◽  
Non Coding Rnas

MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.

scholarly journals Epigenetic Inheritance Underlying Pulmonary Arterial Hypertension

2019 ◽  
Vol 39 (4) ◽  
pp. 653-664 ◽  
Author(s):  
Claudio Napoli ◽  
Giuditta Benincasa ◽  
Joseph Loscalzo
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Disease Onset ◽  
Later Life ◽  
Epigenetic Changes ◽  
Apoptosis Resistance ◽  
Integrated Network ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial

In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.

NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy

2019 ◽  
Vol 133 (9) ◽  
pp. 1085-1096 ◽  
Author(s):  
Xue-liang Zhou ◽  
Zhi-bo Liu ◽  
Rong-rong Zhu ◽  
Huang Huang ◽  
Qi-rong Xu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Metabolic Reprogramming ◽  
Mineral Absorption ◽  
Right Ventricle Dysfunction ◽  
Trehalose Metabolism ◽  
Pulmonary Arterial

Abstract Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC–MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC–MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.

scholarly journals Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: considerations for use in pulmonary vascular disease

2020 ◽  
Vol 55 (3) ◽  
pp. 1901313 ◽  
Author(s):  
Corey E. Ventetuolo ◽  
Jason M. Aliotta ◽  
Julie Braza ◽  
Havovi Chichger ◽  
Mark Dooner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Pulmonary Artery ◽  
Pulmonary Artery Catheter ◽  
Tube Formation ◽  
Cell Phenotype ◽  
Pulmonary Vascular Disease ◽  
Right Heart Catheterisation ◽  
Pulmonary Arterial ◽  
Vessel Networks

Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis.

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