Abstract 410: Interleukin-21 Promotes Pulmonary Arterial Hypertension Through M2 Macrophage Polarization

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yoshikazu Nakaoka ◽  
Takahiro Hashimoto-Kataoka ◽  
Mikiyasu Shirai ◽  
Yasushi Sakata
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Animal Experiments ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Pulmonary Arterial ◽  
M2 Macrophage Polarization

Interleukin-6 (IL-6) is a multifunctional proinflammatory cytokine that is elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a novel downstream target of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis may be a novel potential target for treating PAH.

scholarly journals Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension

2015 ◽  
Vol 112 (20) ◽  
pp. E2677-E2686 ◽  
Author(s):  
Takahiro Hashimoto-Kataoka ◽  
Naoki Hosen ◽  
Takashi Sonobe ◽  
Yoh Arita ◽  
Taku Yasui ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Animal Experiments ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Signaling Axis ◽  
Pulmonary Arterial

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6–mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti–IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21–signaling axis may be a potential target for treating PAH.

scholarly journals Phenotype and function of macrophage polarization in monocrotaline-induced pulmonary arterial hypertension rat model

2021 ◽  
Author(s):  
Yong Fan ◽  
Yanjie Hao ◽  
Dai Gao ◽  
Lan Gao ◽  
Guangtao Li ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Rat Model ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages induced endothelial cell apoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell. These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

scholarly journals Profiling and Molecular Mechanism Analysis of Long Non-Coding RNAs and mRNAs in Pulmonary Arterial Hypertension Rat Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiqiang Hou ◽  
Dandan Chen ◽  
Jie Liu ◽  
Shasha Chen ◽  
Xiaochun Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Expression Profiles ◽  
Macrophage Polarization ◽  
Mechanism Analysis ◽  
Rat Models ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Pulmonary arterial hypertension (PAH) is an immune-mediated disease with poor prognosis and associated with various inflammatory immune diseases. In fact, its pathogenesis is far from clear. Although long non-coding RNAs (lncRNAs) have been implicated in PAH, the molecular mechanisms remain largely unknown. For the first time, in lungs of monocrotaline-induced PAH rat models, we simultaneously detected the expression profiles of lncRNAs and mRNAs by high-throughput sequencing, and explored their roles with bioinformatics analysis and cell assay to discover more potential pathogenesis about PAH. Our data identified that a total of 559 lncRNAs and 691 mRNAs were differentially expressed in lungs during the pathogenesis of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that these dysregulated lncRNAs and mRNAs participated in important biological processes and pathways of PAH, among which inflammatory and immune responses represented the chief enriched pathway. The lncRNA-mRNA co-expression network was developed to uncover the hidden interactions between lncRNAs and mRNAs. Further, the expression levels of lncRNAs (NONRATT018084.2, NONRATT009275.2, NONRATT007865.2, and NONRATT026300.2) and mRNAs (LGALS3, PDGFC, SERPINA1, and NFIL3) were confirmed using quantitative real-time PCR. In the end, lncRNA NONRATT009275.2 could facilitate macrophage polarization to M2 type and be involved in inflammatory immune response. In conclusion, this study provided candidate drug targets and potential roles on lncRNAs in the pathogenesis of PAH, and several key regulatory genes were identified, which laid the initial foundation for further mechanism study in PAH.

scholarly journals Elucidation of the mechanisms and molecular targets of Qishen Yiqi formula for the treatment of pulmonary arterial hypertension using a bioinformatics/network topology-based strategy

2020 ◽  
Vol 23 ◽  
Author(s):  
Peiliang Wu ◽  
Xiaona Xie ◽  
Mayun Chen ◽  
Junwei Sun ◽  
Luqiong Cai ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Network Topology ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Bioactive Ingredients ◽  
Pulmonary Arterial

Background and Objective: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. Methods: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. Results: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. Conclusion: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.

scholarly journals The effect of the WKYMVm peptide on promoting mBMSC secretion of exosomes to induce M2 macrophage polarization through the FPR2 pathway

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Wenbo Zhao ◽  
Junxian Hu ◽  
Qingyi He
Keyword(s):  
Western Blotting ◽  
Macrophage Polarization ◽  
Bone Defects ◽  
The Other ◽  
Formyl Peptide Receptor ◽  
Cell Counting ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Lysosomal Activity ◽  
M2 Macrophage Polarization

Abstract Background When multicystic vesicles (precursors of exosomes) are formed in cells, there are two results. One is decomposition by lysosomes, and the other is the generation of exosomes that are transported out through the transmembrane. On the other hand, M2 macrophages promote the formation of local vascularization and provide necessary support for the repair of bone defects. To provide a new idea for the treatment of bone defects, the purpose of our study was to investigate the effect of WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met-NH2) peptide on the secretion of exosomes from murine bone marrow-derived MSCs (mBMSCs) and the effect of exosomes on the polarization of M2 macrophages. Methods The WKYMVm peptide was used to activate the formyl peptide receptor 2 (FPR2) pathway in mBMSCs. First, we used Cell Counting Kit-8 (CCK-8) to detect the cytotoxic effect of WKYMVm peptide on mBMSCs. Second, we used western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of interferon stimulated gene 15 (ISG15) and transcription factor EB (TFEB) in mBMSCs. Then, we detected lysosomal activity using a lysozyme activity assay kit. Third, we used an exosome extraction kit and western blotting to detect the content of exosomes secreted by mBMSCs. Fourth, we used immunofluorescence and western blotting to count the number of polarized M2 macrophages. Finally, we used an inhibitor to block miRNA-146 in exosomes secreted by mBMSCs and counted the number of polarized M2 macrophages. Results We first found that the WKYMVm peptide had no toxic effect on mBMSCs at a concentration of 1 μmol/L. Second, we found that when the FPR2 pathway was activated by the WKYMVm peptide in mBMSCs, ISG15 and TFEB expression was decreased, leading to increased secretion of exosomes. We also found that lysosomal activity was decreased when the FPR2 pathway was activated by the WKYMVm peptide in mBMSCs. Third, we demonstrated that exosomes secreted by mBMSCs promote the polarization of M2 macrophages. Moreover, all these effects can be blocked by the WRWWWW (WRW4, H-Trp-Arg-Trp-Trp-Trp-Trp-OH) peptide, an inhibitor of the FPR2 pathway. Finally, we confirmed the effect of miRNA-146 in exosomes secreted by mBMSCs on promoting the polarization of M2 macrophages. Conclusion Our findings demonstrated the potential value of the WKYMVm peptide in promoting the secretion of exosomes by mBMSCs and eventually leading to M2 macrophage polarization. We believe that our study could provide a research basis for the clinical treatment of bone defects.

Abstract 14880: Single-cell Transcriptomes Identify Unique Endothelial Subpopulation (FABP4 + TMEM100 - ) With Lipid Metabolism Dysfunction in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
BIN LIU ◽  
Jingbo Dai ◽  
Li Shuai ◽  
Dan Yi ◽  
Youyang Zhao ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Single Cell ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Premature Death ◽  
Right Heart Failure ◽  
Fatty Acid Binding ◽  
Pulmonary Arterial ◽  
Endothelial Plasticity

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial plasticity or distinct cell populations are critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: Here we applied single-cell RNA sequencing (ScRNA-seq) to profile the pulmonary cells in a severe mouse model ( Egln1 Tie2Cre mice) of PAH. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure FABP4 and FABP5 expression. siRNA mediated knockdown of FABP4 and FABP5 was performed to study cell proliferation and apoptosis. Mice with Fabp4 and Fabp5 deletion ( Fabp45 -/- ) and wild type (WT) mice were incubated with hypoxia (10% O 2 ) to induced PAH. Egln1 Tie2Cre mice were bred with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. Results: We identified five distinct EC subpopulations in both WT and Egln1 Tie2Cre mice via scRNA-seq. Unexpectedly, the number of Cluster (EC2, 49.8%) was markedly increased in Egln1 Tie2Cre lung compared with WT lung (2.8%). EC2 cluster (mainly from Egln1 Tie2Cre lung) was characterized by little expression of Tmem100 , Cldn5 , Tspan7 , Calcrl and Foxf1 and high expression of Fabp4, Cdh13, Sparl1 and Fabp5 . Fatty acid-binding protein (FABP) 4 and FABP5 (FABP4-5) were highly induced in PAECs from IPAH patients. Knockdown of FABP4-5 reduced EC proliferation and starvation-induced Caspase 3/7 activity. Fabp45 -/- mice were protected from hypoxia-induced PAH compared to WT mice. Moreover, Egln1 Tie2Cre / Fabp45 -/- mice also exhibited a reduction of RVSP and RV hypertrophy compared to Egln1 Tie2Cre mice. Conclusions: ScRNA-seq analysis identifies a unique endothelial population (FABP4 + TMEM100 - ) highly enriched in the lung of severe PAH mice. Knockdown of FABP4-5 reduces EC proliferation starvation-induced injury. Genetic deletion of FABP4-5 protects from hypoxia and Egln1 deficiency-induced PAH in mice.

Abstract 263: Differential Effects of 17ß-Estradiol and 16a-Hydroxyestrone in Oxidative Stress and Proliferative Responses in Human Pulmonary Artery Smooth Muscle Cells - Implications in Pulmonary Arterial Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Katie Y Hood ◽  
Augusto C Montezano ◽  
Margaret R MacLean ◽  
Rhian M Touyz
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Cell Growth ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Antioxidant Systems ◽  
Ros Generation ◽  
Ros Production ◽  
Differential Effects ◽  
Pulmonary Arterial

Women develop pulmonary arterial hypertension (PAH) more frequently than men. This may relate, in part, to metabolism of 17β-estradiol (E2), leading to formation of the deleterious metabolite, 16α-hydroxyestrone (16α OHE1), which plays a role in the remodelling of pulmonary arteries. Molecular mechanisms whereby 16αOHE1 influences PASMC remodelling are unclear but ROS may be important, since oxidative stress has been implicated in the pathogenesis of PAH. We hypothesised that E2 and 16αOHE1 leads to Nox-induced ROS production, which promotes PASMC damage. Cultured PASMCs were stimulated with either E2 (1nM) or 16αOHE1 (1nM) in the presence/absence of EHT1864 (100μM, Rac1 inhibitor) or tempol (antioxidant; 10μM). ROS production was assessed by chemiluminescence (O2-) and Amplex Red (H2O2). Antioxidants (thioredoxin, peroxiredoxin 1 and NQ01), regulators of Nrf2 (BACH1, Nrf2) and, marker of cell growth (PCNA) were determined by immunoblotting. E2 increased O2- production at 4h (219 ± 30% vs vehicle; p<0.05), an effect blocked by EHT1864 and tempol. E2 also increased H2O2 generation (152 ± 4%; p<0.05). Thioredoxin, NQ01 and peroxiredoxin1 (71 ± 6%; 78 ± 9%; 69 ± 8%; p<0.05 respectively) levels were decreased by E2 as was PCNA expression (72 ± 2%; p<0.05). 16αOHE1 exhibited a rapid (5 min) and exaggerated increase in ROS production (355 ± 41%; p<0.05), blocked by tempol and EHT1864. This was associated with an increase in Nox4 expression (139 ± 11% vs vehicle, p<0.05). 16αOHE1 increased BACH1, (129 ± 3%; p<0.05), a competitor of Nrf2, which was decreased (92 ± 2%). In contrast, thioredoxin expression was increased by 16aOHE1 (154 ± 22%; p<0.05). PCNA (150 ± 5%) expression was also increased after exposure to 16αOHE1. In conclusion, E2 and 16αOHE1 have differential effects on redox processes associated with PASMC growth. Whereas E2 stimulates ROS production in a slow and sustained manner without effect on cell growth, 16αOHE1 upregulates Nox4 with associated rapid increase in ROS generation and downregulation of antioxidant systems, affecting proliferation. Our findings suggest that E2 -derived metabolites may promote a pro-proliferative PASMC phenotype through Nox4-derived ROS generation. These deleterious effects may impact on vascular remodeling in PAH.

scholarly journals Pathophysiology, incidence, management, and consequences of cardiac arrhythmia in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

2019 ◽  
Vol 9 (1) ◽  
pp. 204589401983489 ◽  
Author(s):  
Meghan M. Cirulis ◽  
John J. Ryan ◽  
Stephen L. Archer
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Outcome Data ◽  
Current Evidence ◽  
Clinical Aspects ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial

Arrhythmias are increasingly recognized as serious, end-stage complications of pre-capillary pulmonary hypertension, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Although arrhythmias contribute to symptoms, morbidity, in-hospital mortality, and possibly sudden death in PAH/CTEPH, there remains a paucity of epidemiologic, pathophysiologic, and outcome data to guide management of these patients. This review summarizes the most current evidence on the topic: from the molecular mechanisms driving arrhythmia in the hypertrophied or failing right heart, to the clinical aspects of epidemiology, diagnosis, and management.

scholarly journals ILC2 Proliferated by IL-33 Stimulation Alleviates Acute Colitis in Rag1-/- Mouse through Promoting M2 Macrophage Polarization

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yong You ◽  
Xiaoqing Zhang ◽  
Xiao Wang ◽  
Dan Yue ◽  
Fanxiang Meng ◽  
...  
Keyword(s):  
Body Weight ◽  
Macrophage Polarization ◽  
Epithelial Barrier ◽  
M2 Macrophage ◽  
Surface Markers ◽  
M2 Macrophages ◽  
Immunological Function ◽  
Innate Lymphoid Cell ◽  
Acute Colitis ◽  
M2 Macrophage Polarization

This study was to identify functions of ILC2, a newly found innate lymphoid cell which mainly locates in mucosa organs like lungs and intestines, in IBD. We injected rIL-33 protein to C57/BL6 mouse to explore how IL-33 induces ILC2 proliferation. The results showed that ILC2 reached a proliferation peak at day 5 and expressed multiple surface markers like CD127, C-kit, CD69, CD44, ST2, CD27, DR3, MHCII, and CD90.2. ILC2 also expressed high quantity of IL-13 and IL-5 and few IL-17A which indicates a potentially immunological function in IBD development. Afterwards, we transferred sort purified ILC2 to Rag1-/- mouse given DSS to induce acute colitis in order to explore the innate function of ILC2. Data showed that ILC2 alleviates DSS-induced acute innate colitis by repairing epithelial barrier and restore body weight. Furthermore, we found that ILC2 can cause macrophages polarizing to M2 macrophages in the gut. Therefore, we concluded that ILC2 played a therapeutic role in mouse acute colitis.

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