Updated classification of pulmonary hypertension. The World Health Organization classifies PH into five groups based on the underlying etiology. Group I includes PAH. Group II refers to PH from left sided heart disease. Group III refers to PH caused by chronic hypoxia lung disease. Group IV is associated with chronic blood clots, and Group V includes all other forms of PH associated with unclear multifactorial mechanisms such as sarcoidosis and hematological disorders.

Updated classification of pulmonary hypertension. The World Health Organization classifies PH into five groups based on the underlying etiology. Group I includes PAH. Group II refers to PH from left sided heart disease. Group III refers to PH caused by chronic hypoxia lung disease. Group IV is associated with chronic blood clots, and Group V includes all other forms of PH associated with unclear multifactorial mechanisms such as sarcoidosis and hematological disorders.

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Pulmonary arterial hypertension (PAH) is a multifactorial cardiopulmonary disease characterized by an elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which can lead to right ventricular (RV) failure, multi-organ dysfunction, and ultimately to premature death. Despite the advances in molecular biology, the mecha...

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... World Health Organization classifies PH into five groups based on the underlying etiology (8) (Fig. 2). Group 1 (PAH) refers to idiopathic or inherited PAH, drug or toxins induced, connective tissue and heart diseases, capillary hemangiomatosis, pulmonary veno-occlusive disease, and PH of the newborn (8). The term PH is used for all the other groups of the classification: group 2, 3, 4, and 5. Left heart-associated diseases are ...

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... Existing studies have determined that gene expression in PAH is also regulated by epigenetic factors, including DNA methylation, interference of microRNAs and histone modification, but these processes do not change the sequence of genes [30,31]. In 2010, Archer et al. 's [32] investigation first demonstrated that epigenetic deficiency of superoxide dismutase (SOD)-2 due to gene methylation in an enhancer region of intron 2 and in the Fig. 1 Schematic diagram of pulmonary vascular remodelling. ...
... Ultimately, histone modification by acetylation and methylation of specific amino acids influences the development of PAH by regulating gene transcriptional activity and gene expression. Histones, the primary components of chromatin, directly modulate the expression pattern of genes [31]. Existing evidence also shows that histone deacetylase (HDAC) inhibitors might represent promising and emerging therapeutic targets in PAH. ...
... Hence, whether and how the active natural ingredients mediate microRNA and lncRNA function for regulating downstream signalling should also be further investigated. In addition to the aforementioned natural drug therapies, increasing novel and promising therapeutic approaches have been identified, such as enhancing apoptosis of PASMCs and HPAECs, targeting microRNA and lncRNAs, stem cell-based therapies and epigenetic medicines, or even gene transfer [31,166]. In addition, despite abundant clinical research of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors in the management of PAH are ongoing, but some clinical trial protocols are less rigorous, including unsuitable end-points without consideration of biomarkers according to the biological characteristics of PAH progression [167]. ...
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Pulmonary arterial hypertension (PAH) is a progressive and rare disease without obvious clinical symptoms that shares characteristics with pulmonary vascular remodeling. Right heart failure in the terminal phase of PAH seriously threatens the lives of patients. This review attempts to comprehensively outline the current state of knowledge on PAH its pathology, pathogenesis, natural medicines therapy, mechanisms and clinical studies to provide potential treatment strategies. Although PAH and pulmonary hypertension have similar pathological features, PAH exhibits significantly elevated pulmonary vascular resistance caused by vascular stenosis and occlusion. Currently, the pathogenesis of PAH is thought to involve multiple factors, primarily including genetic/epigenetic factors, vascular cellular dysregulation, metabolic dysfunction, even inflammation and immunization. Yet many issues regarding PAH need to be clarified, such as the “oestrogen paradox”. About 25 kinds monomers derived from natural medicine have been verified to protect against to PAH via modulating BMPR2/Smad, HIF-1α, PI3K/Akt/mTOR and eNOS/NO/cGMP signalling pathways. Yet limited and single PAH animal models may not corroborate the efficacy of natural medicines, and those natural compounds how to regulate crucial genes, proteins and even microRNA and lncRNA still need to put great attention. Additionally, pharmacokinetic studies and safety evaluation of natural medicines for the treatment of PAH should be undertaken in future studies. Meanwhile, methods for validating the efficacy of natural drugs in multiple PAH animal models and precise clinical design are also urgently needed to promote advances in PAH. Graphical Abstract
... MiR-17 promotes the STAT3-BMPR pathway, whereas miR-145 inhibits BMPR activity MiR-30, MiR-22, and let-7f were down regulated in both hypoxic and monocrotaline models, however miR-322 and miR-451 were significantly up regulated throughout the progression of PAH. In PASMCs from people with PAH, miR-204 was consistently down regulated [26,28]. Absence of regulation of miR-17 in PASMCs has been linked to PAH and is likely to DOI: http://dx.doi.org/10.5772/intechopen.107471 ...
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Endothelial dysfunction and vascular remodeling are the hallmarks of pulmonary arterial hypertension (PAH). For PAH treatment, there is a rising demand of Stem cell therapy. Interestingly, research reveals that stem/progenitor cells may have an impact in disease progression and therapy in PAH patients. Clinical trials for stem cell therapy in cardiac cell regeneration for heart repair in PAH patients are now underway. The clinical potential of stem/progenitor cell treatment that offers to PAH patients helps in lesion formation which occurs through regaining of vascular cell activities. Majorly the stem cells which are specifically derived from bone marrow such as mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and induced pluripotent cells (iPSCs), adipose-derived stem cells (ADSCs), and cardiac stromal cells (CSCs) are among the subtypes that are proved to play a pivotal role in the repair of the heart. But with only MSCs and EPCs, have shown positive outcomes and act as therapeutically efficient in regaining cure for PAH in clinical trials. This chapter also seeks to explain the potential limitations and challenges with most recent achievements in stem/progenitor cell research in PAH.
... Considering PRC2's role in epigenetic regulation of downstream gene expression, its catalytic subunit EZH2 has emerged as a therapeutic target of interest. EZH2 overexpression and gain-of-function mutations are associated with aberrantly high H3K27 trimethylation levels and repression of target genes related to cell cycle progression, proliferation, apoptosis, autophagy, senescence, and inflammation (29)(30)(31). As a result, further studies have associated dysregulation of EZH2 with various diseases, including CVD (cardiac hypertrophy, fibrosis, atherosclerosis, ischemic heart disease, myocardial regeneration, cardiomyopathy, pulmonary arterial hypertension, atrial fibrillation) (26,(32)(33)(34)(35)(36)(37), various solid cancers (lung, breast, endometrial, ovarian, nasopharyngeal, thyroid, liver, prostate, and glioblastoma) (8,17,(38)(39)(40), as well as hematopoietic cancers (Non-Hodgkin's, large B-cell, and follicular lymphoma) (41,42). ...
... As a result, further studies have associated dysregulation of EZH2 with various diseases, including CVD (cardiac hypertrophy, fibrosis, atherosclerosis, ischemic heart disease, myocardial regeneration, cardiomyopathy, pulmonary arterial hypertension, atrial fibrillation) (26,(32)(33)(34)(35)(36)(37), various solid cancers (lung, breast, endometrial, ovarian, nasopharyngeal, thyroid, liver, prostate, and glioblastoma) (8,17,(38)(39)(40), as well as hematopoietic cancers (Non-Hodgkin's, large B-cell, and follicular lymphoma) (41,42). Preclinical studies investigating inhibition of EZH2, primarily with inhibitors GSK126 and EPZ6437 (Tazemetostat), have been promising in both CVD and cancer (30,39,(43)(44)(45)(46)(47) and have led to early phase clinical trials in the context of various lymphomas and advanced solid tumors (NCT01897571), mesothelioma (NCT02860286), sarcoma (NCT02601950). Importantly, our report emphasizes the importance of characterizing the exosomal protein and RNA cargo to understand better how astronaut-derived exosomes affect histone modifications, gene expression, and biological responses in recipient cells. ...
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There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3–chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.
... Sustained vascular remodeling is associated with arterial stiffening, thickening, and increased pulmonary vascular resistance (PVR) [77]. If left untreated, these vascular changes can lead to right ventricle (RV) failure and the death of the patient [78,79]. Most of the FDA-approved therapies currently available for PAH target the imbalance between vasoconstrictor and vasodilator agents and endothelial cell function. ...
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Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells or tissues to restore physiological protein expression and/or activity. In this review, we review (1) different types of viral and non-viral vectors as well as gene-editing techniques; and (2) the application of gene therapy for the treatment of respiratory diseases and disorders, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, non-small-cell lung cancer, and COVID-19. Further, we also provide specific examples of lung-targeted therapies and discuss the major limitations of gene therapy.
... LncRNAs are implicated in a variety of disease processes, including neurocognitive, cardiovascular diseases, and cancers. In cardiovascular disease, lncRNAs play a role in cardiac hypertrophy, myocardial infarction, heart failure, and pulmonary hypertension (Lozano-Vidal et al., 2019;Bisserier et al., 2020) and have been described as potential biomarkers or therapeutic agents for heart disease, including myocardial infarction, coronary artery disease, heart failure, and diabetic cardiomyopathy (Yang et al., 2014;Rizki and Boyer, 2015). Regarding cancer, several lncRNAs are differentially expressed in breast, colorectal, and colon cancer, as well as melanoma (Kino et al., 2010;Poliseno et al., 2010;Marín-Béjar et al., 2013;Huarte, 2015). ...
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During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts’ health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998–2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log 2 fold change, with molecular, cellular, and clinical implications.
... An epigenetic regulation of gene expression has been implicated in the pathogenesis of PH [12,13]. Histone and non-histone protein acetylation is regulated via the activation of acetyltransferases (HAT) and deacetylases (HDAC) and is fundamental to diseaseassociated changes in vascular and cardiac cell phenotypes [12,14]. ...
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Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.
... During the past decade, a large body of evidence demonstrated that epigenetic mechanisms, such as DNA or histone modifications, play a critical role in the regulation of gene expression in several diseases. [20][21][22][23][24] DNA methylation may induce structural changes in chromatin structure by recruiting MeCPs (methyl CpG [5'-C-phosphate-G-3']-binding proteins) and HDAC (histone deacetylase). These structural changes prevent the binding of transcription factors (TF) and subsequent transcription initiations. ...
... These structural changes prevent the binding of transcription factors (TF) and subsequent transcription initiations. [24][25][26] MeCPs have also been shown to interact with DNA methyltransferases (DNMT). Abnormal DNMT and MeCP2 expression can affect the DNA methylation level and therefore contribute to disease phenotype. ...
... In PAH, vascular remodeling is characterized by enhanced proliferation, migration, and reduced apoptosis of pulmonary vascular cells. 24 To determine whether SIN3a directly regulates vascular cell growth, we used a loss-of-function approach (siRNA SIN3a) to knockdown SIN3a expression ( Figure 3A) and a gain-of-SIN3a-function approach using lentivirus vector-mediated overexpression to increase its expression ( Figure 3D) without any significant changes in SIN3b expression (data not shown). It is important to note that immunoblot analysis revealed that SIN3a silencing represses BMPR2 expression and potentiates CCND1 (cyclin D1) expression ( Figure 3A). ...
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Background: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of Switch-Independent 3a (SIN3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. Methods: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells (hPASMC). Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific Adeno-Associated Virus serotype 1 (AAV1) or a lentivirus encoding for human SIN3a in vivo . Results: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. Interestingly, we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. Interestingly, SIN3a overexpression inhibited hPASMC proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 and EZH2 while promoting the expression of the DNA demethylase TET1. Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF binding to the BMPR2 promoter. Finally, we identified intratracheal delivery of AAV1.hSIN3a to be a beneficial therapeutic approach in PAH- by attenuating pulmonary vascular and RV remodeling, decreasing RVSP and mPAP pressure, and restoring BMPR2 expression in rodent models of PAH. Conclusions: Altogether, our study unveiled the protective/beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in hPASMC. Our study also identified lung-targeted SIN3a gene therapy using AAV1 as a new promising therapeutic strategy for treating patients with PAH.
... In the next section, we will review these most novel mechanisms. To delve into mechanisms not described here, we refer the readers to other reviews [68][69][70][71]. ...
Article
Pulmonary hypertension is a rare disease with high morbidity and mortality which mainly affects women of reproductive age. Despite recent advances in understanding the pathogenesis of pulmonary hypertension, the high heterogeneity in the presentation of the disease among different patients makes it difficult to make an accurate diagnosis and to apply this knowledge to effective treatments. Therefore, new studies are required to focus on translational and personalized medicine to overcome the lack of specificity and efficacy of current management. Here, we review the majority of public databases storing ‘omics‘ data of pulmonary hypertension studies, from animal models to human patients. Moreover, we review some of the new molecular mechanisms involved in the pathogenesis of pulmonary hypertension, including non-coding RNAs and the application of ‘omics’ data to understand this pathology, hoping that these new approaches will provide insights to guide the way to personalized diagnosis and treatment.
... PAH was initially described as a non-treatable disease. However, the recent advances in diagnostic tools, multi-omics technologies, and early treatment have significantly improved patients' quality of life and overall life expectancy [15][16][17]. Current data shows that the median survival was 2.8 years between 1980 and 1991 when no specific and efficient treatments were available, while the median survival is 7-10 years in the modern treatment era [18,19]. ...
Article
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Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.
... Pathophysiologic characteristics of PH include vasoconstriction, thrombosis and inflammation. Pulmonary vascular remodeling is associated with smooth muscle and endothelial cells dysfunction (Bisserier et al., 2020;Shimoda and Laurie, 2013). It is now well established that pulmonary artery endothelial cells (PAECs) play a major role in the regulation of vascular tone, inflammation, and thrombosis. ...
... Over the past decade, accumulated data suggested that epigenetics may play a major role in the setting of PAH (Bisserier et al., 2020;Cheng et al., 2019). Epigenetics is defined as a heritable change to the chromatin resulting in a shift in gene expression without altering the DNA sequence (Weinhold, 2006). ...
Article
Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.