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1
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Mitra A, Yi D, Dai Z, de Jesus Perez V. Unraveling the role of HIF and epigenetic regulation in pulmonary arterial hypertension: implications for clinical research and its therapeutic approach. Front Med (Lausanne) 2024; 11:1460376. [PMID: 39450110 PMCID: PMC11499164 DOI: 10.3389/fmed.2024.1460376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 09/12/2024] [Indexed: 10/26/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment.
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Affiliation(s)
- Ankita Mitra
- Division of Pulmonary and Critical Care, Stanford University, Palo Alto, CA, United States
| | - Dan Yi
- Department of Internal Medicine, University of Arizona College of Medicine Phoenix, Phoenix, AZ, United States
| | - Zhiyu Dai
- Department of Internal Medicine, University of Arizona College of Medicine Phoenix, Phoenix, AZ, United States
- Department of Medicine, Washington University School of Medicine in St. Louis (WashU), St. Louis, MO, United States
| | - Vinicio de Jesus Perez
- Division of Pulmonary and Critical Care, Stanford University, Palo Alto, CA, United States
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2
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Wang S, Awad KS, Chen LY, Siddique MAH, Ferreyra GA, Wang CL, Joseph T, Yu ZX, Takeda K, Demirkale CY, Zhao YY, Elinoff JM, Danner RL. Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α. Am J Physiol Lung Cell Mol Physiol 2024; 327:L503-L519. [PMID: 39159362 PMCID: PMC11482463 DOI: 10.1152/ajplung.00077.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/16/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024] Open
Abstract
In hypoxic and pseudohypoxic rodent models of pulmonary hypertension (PH), hypoxia-inducible factor (HIF) inhibition attenuates disease initiation. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PH in humans, indicating the involvement of other mechanisms. Given the association between endothelial cell dysfunction and PH, the effects of pseudohypoxia and its underlying pathways were investigated in primary human lung endothelial cells. PHD2 silencing or inhibition, while activating HIF2α, induced apoptosis-resistance and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activated AKT and ERK, inhibited JNK, and reduced AIP1 (ASK1-interacting protein 1), all independent of HIF2α. Like PHD2, AIP1 silencing affected these same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was partially reversed by AKT inhibition. Consistent with these in vitro findings, AIP1 protein levels in lung endothelial cells were decreased in Tie2-Cre/Phd2 knockout mice compared with wild-type controls. Lung vascular endothelial cells from patients with pulmonary arterial hypertension (PAH) showed IFN/STAT activation. Lung tissue from both SU5416/hypoxia PAH rats and patients with PAH all showed AKT activation and dysregulated AIP1 expression. In conclusion, PHD2 deficiency in lung vascular endothelial cells drives an apoptosis-resistant and inflammatory phenotype, mediated by AKT activation and AIP1 loss independent of HIF signaling. Targeting these pathways, including PHD2, AKT, and AIP1, holds the potential for developing new treatments for endothelial dysfunction in PH.NEW & NOTEWORTHY HIF activation alone does not conclusively lead to human PH, suggesting that HIF-independent signaling may also contribute to hypoxia-induced PH. This study demonstrated that PHD2 silencing-induced pseudohypoxia in human lung endothelial cells suppresses apoptosis and activates STAT, effects that persist despite HIF2α inhibition or knockdown and are attributed to AKT and ERK activation, JNK inhibition, and AIP1 loss. These findings align with observations in lung endothelial cells and tissues from PAH rodent models and patients.
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Affiliation(s)
- Shuibang Wang
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
| | - Keytam S Awad
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
| | - Li-Yuan Chen
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Mohammad A H Siddique
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Gabriela A Ferreyra
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
| | - Caroline L Wang
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
| | - Thea Joseph
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Zu-Xi Yu
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Kazuyo Takeda
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Cumhur Y Demirkale
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
| | - You-Yang Zhao
- Section for Injury Repair and Regeneration, Stanley Manne Children Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - Jason M Elinoff
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Robert L Danner
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
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3
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Sun MR, Gonzalez S, Huang JB, Zhou Q, Cherukuri A, Adavadkar R, Yan HL, Sun SH, Zhou G, Raj JU, Chen T. Biphasic regulation of miR-17∼92 transcription during hypoxia: roles of HIF1 and p53 hyperphosphorylation at ser15. Am J Physiol Lung Cell Mol Physiol 2024; 327:L102-L113. [PMID: 38501173 PMCID: PMC11380943 DOI: 10.1152/ajplung.00127.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 03/20/2024] Open
Abstract
We have reported previously that during hypoxia exposure, the expression of mature miR-17∼92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here, we investigated the mechanisms regulating this biphasic expression of miR-17∼92 in PASMC in hypoxia. We measured the level of primary miR-17∼92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3% O2, 6 h) induced the level of primary miR-17∼92, whereas long-term hypoxia exposure (3% O2, 24 h) decreased its level, suggesting a biphasic regulation of miR-17∼92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17∼92 was hypoxia-inducible factor 1α (HIF1α) and E2F1 dependent. Two HIF1α binding sites on miR-17∼92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17∼92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17∼92 promoter increased miR-17∼92 promoter activity in both normoxia and hypoxia. Our findings suggest that the biphasic transcriptional regulation of miR-17∼92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induce the transcription of miR-17∼92, whereas during long-term hypoxia exposure, hyperphosphorylation of p53 suppresses the expression of miR-17∼92.NEW & NOTEWORTHY We showed that the biphasic transcriptional regulation of miR-17∼92 during hypoxia is controlled by two distinct mechanisms: during short-term hypoxia exposure, induction of HIF1 and E2F1 upregulates miR-17∼92. Longer hypoxia exposure induces hyperphosphorylation of p53 at ser15, which leads to its binding to miR-17∼92 promoter and inhibition of its expression. Our findings provide novel insights into the spatiotemporal regulation of miR-17∼92 that may play a role in the development of human lung diseases including pulmonary hypertension (PH).
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Affiliation(s)
- Miranda R Sun
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Susana Gonzalez
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Jason B Huang
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Qiyuan Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Arjun Cherukuri
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Rohan Adavadkar
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Hong-Li Yan
- Department of Medical Genetics, Second Military Medical University, Shanghai, People's Republic of China
| | - Shu-Han Sun
- Department of Medical Genetics, Second Military Medical University, Shanghai, People's Republic of China
| | - Guofei Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
- University of Illinois Cancer Center, Chicago, Illinois, United States
| | - J Usha Raj
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
- Children's Hospital University of Illinois, University of Illinois Hospital and Health Sciences System, Chicago, Illinois, United States
| | - Tianji Chen
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
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Ahmed ASI, Blood AB, Zhang L. Hypoxia-induced pulmonary hypertension in adults and newborns: implications for drug development. Drug Discov Today 2024; 29:104015. [PMID: 38719143 PMCID: PMC11936511 DOI: 10.1016/j.drudis.2024.104015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/18/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024]
Abstract
Chronic hypoxia-induced pulmonary hypertension (CHPH) presents a complex challenge, characterized by escalating pulmonary vascular resistance and remodeling, threatening both newborns and adults with right heart failure. Despite advances in understanding the pathobiology of CHPH, its molecular intricacies remain elusive, particularly because of the multifaceted nature of arterial remodeling involving the adventitia, media, and intima. Cellular imbalance arises from hypoxia-induced mitochondrial disturbances and oxidative stress, reflecting the diversity in pulmonary hypertension (PH) pathology. In this review, we highlight prominent mechanisms causing CHPH in adults and newborns, and emerging therapeutic targets of potential pharmaceuticals.
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Affiliation(s)
- Abu Shufian Ishtiaq Ahmed
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
| | - Arlin B Blood
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
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5
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Saddouk FZ, Kuzemczak A, Saito J, Greif DM. Endothelial HIFα/PDGF-B to smooth muscle Beclin1 signaling sustains pathological muscularization in pulmonary hypertension. JCI Insight 2024; 9:e162449. [PMID: 38652543 PMCID: PMC11141934 DOI: 10.1172/jci.insight.162449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 04/17/2024] [Indexed: 04/25/2024] Open
Abstract
Mechanisms underlying maintenance of pathological vascular hypermuscularization are poorly delineated. Herein, we investigated retention of smooth muscle cells (SMCs) coating normally unmuscularized distal pulmonary arterioles in pulmonary hypertension (PH) mediated by chronic hypoxia with or without Sugen 5416, and reversal of this pathology. With hypoxia in mice or culture, lung endothelial cells (ECs) upregulated hypoxia-inducible factor 1α (HIF1-α) and HIF2-α, which induce platelet-derived growth factor B (PDGF-B), and these factors were reduced to normoxic levels with re-normoxia. Re-normoxia reversed hypoxia-induced pulmonary vascular remodeling, but with EC HIFα overexpression during re-normoxia, pathological changes persisted. Conversely, after establishment of distal muscularization and PH, EC-specific deletion of Hif1a, Hif2a, or Pdgfb induced reversal. In human idiopathic pulmonary artery hypertension, HIF1-α, HIF2-α, PDGF-B, and autophagy-mediating gene products, including Beclin1, were upregulated in pulmonary artery SMCs and/or lung lysates. Furthermore, in mice, hypoxia-induced EC-derived PDGF-B upregulated Beclin1 in distal arteriole SMCs, and after distal muscularization was established, re-normoxia, EC Pdgfb deletion, or treatment with STI571 (which inhibits PDGF receptors) downregulated SMC Beclin1 and other autophagy products. Finally, SMC-specific Becn1 deletion induced apoptosis, reversing distal muscularization and PH mediated by hypoxia with or without Sugen 5416. Thus, chronic hypoxia induction of the HIFα/PDGF-B axis in ECs is required for non-cell-autonomous Beclin1-mediated survival of pathological distal arteriole SMCs.
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MESH Headings
- Animals
- Humans
- Male
- Mice
- Arterioles/metabolism
- Arterioles/pathology
- Autophagy
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Beclin-1/metabolism
- Beclin-1/genetics
- Disease Models, Animal
- Endothelial Cells/metabolism
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/genetics
- Hypoxia/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Indoles
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Proto-Oncogene Proteins c-sis/metabolism
- Proto-Oncogene Proteins c-sis/genetics
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Pyrroles
- Signal Transduction
- Vascular Remodeling
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Affiliation(s)
- Fatima Z. Saddouk
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Andrew Kuzemczak
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Junichi Saito
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Daniel M. Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
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6
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Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 2024; 23:175-200. [PMID: 38123660 DOI: 10.1038/s41573-023-00848-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 12/23/2023]
Abstract
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Wei Ruan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bentley Bobrow
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Holger K Eltzschig
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- Outcomes Research Consortium, Cleveland, OH, USA.
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Kim H, Liu Y, Kim J, Kim Y, Klouda T, Fisch S, Baek SH, Liu T, Dahlberg S, Hu CJ, Tian W, Jiang X, Kosmas K, Christou HA, Korman BD, Vargas SO, Wu JC, Stenmark KR, Perez VDJ, Nicolls MR, Raby BA, Yuan K. Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling. EMBO Rep 2024; 25:616-645. [PMID: 38243138 PMCID: PMC10897382 DOI: 10.1038/s44319-023-00054-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 01/21/2024] Open
Abstract
Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
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Affiliation(s)
- Hyunbum Kim
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yu Liu
- Stanford Cardiovascular Institute; Department of Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Jiwon Kim
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yunhye Kim
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Timothy Klouda
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sudeshna Fisch
- Department of Medicine, Brigham and Women Hospital, Boston, MA, USA
| | - Seung Han Baek
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tiffany Liu
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Suzanne Dahlberg
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Cheng-Jun Hu
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Wen Tian
- Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Stanford University, Stanford, CA, USA
| | - Xinguo Jiang
- Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Stanford University, Stanford, CA, USA
| | - Kosmas Kosmas
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Helen A Christou
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Benjamin D Korman
- Division of Allergy/Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Sara O Vargas
- Division of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute; Department of Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Kurt R Stenmark
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Vinicio de Jesus Perez
- Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Stanford University, Stanford, CA, USA
| | - Mark R Nicolls
- Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Stanford University, Stanford, CA, USA
| | - Benjamin A Raby
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ke Yuan
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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8
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He J, Jia Z, Zhang A, Bai M. Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns. Pediatr Nephrol 2024; 39:37-48. [PMID: 37284874 DOI: 10.1007/s00467-023-06031-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/28/2023] [Accepted: 05/15/2023] [Indexed: 06/08/2023]
Abstract
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in several countries as a supplement or even an alternative to the clinical treatment of anemia in patients with chronic kidney disease (CKD). Activation of HIF by HIF-PHIs effectively increases hemoglobin (Hb) level in CKD patients by inducing multiple HIF downstream signaling pathways. This indicates that HIF-PHIs have effects beyond erythropoietin, while their potential benefits and risks should be necessarily assessed. Multiple clinical trials have largely demonstrated the efficacy and safety of HIF-PHIs in the short-term treatment of anemia. However, in terms of long-term administration, especially over 1 year, the benefits and risks of HIF-PHIs still need to be assessed. Particular attention should be paid to the risk of kidney disease progression, cardiovascular events, retinal diseases, and tumor risk. This review aims to summarize the current potential risks and benefits of HIF-PHIs in CKD patients with anemia and further discuss the mechanism of action and pharmacological properties of HIF-PHIs, in order to provide direction and theoretical support for future studies.
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Affiliation(s)
- Jia He
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China
| | - Zhanjun Jia
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
| | - Aihua Zhang
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
| | - Mi Bai
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China.
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9
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Barnes EA, Ito R, Che X, Alvira CM, Cornfield DN. Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2023; 325:L741-L755. [PMID: 37847687 PMCID: PMC11068430 DOI: 10.1152/ajplung.00428.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 09/21/2023] [Accepted: 10/11/2023] [Indexed: 10/19/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.
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Affiliation(s)
- Elizabeth A Barnes
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Reiji Ito
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Xibing Che
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Cristina M Alvira
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - David N Cornfield
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
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Barnes EA, Knutsen C, Kindt A, Che X, Ying L, Adams E, Gonzalez E, Oak P, Hilgendorff A, Alvira CM, Cornfield DN. Hypoxia-Inducible Factor-1α in SM22α-Expressing Cells Modulates Alveolarization. Am J Respir Cell Mol Biol 2023; 69:470-483. [PMID: 37290124 PMCID: PMC10557922 DOI: 10.1165/rcmb.2023-0045oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/08/2023] [Indexed: 06/10/2023] Open
Abstract
Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia, remains high. Infants with bronchopulmonary dysplasia have larger and fewer alveoli, a lung pathology that can persist into adulthood. Although recent data point to a role for hypoxia-inducible factor-1α (HIF-1α) in mediating pulmonary angiogenesis and alveolarization, the cell-specific role of HIF-1α remains incompletely understood. Thus, we hypothesized that HIF-1α, in a distinct subset of mesenchymal cells, mediates postnatal alveolarization. To test the hypothesis, we generated mice with a cell-specific deletion of HIF-1α by crossing SM22α promoter-driven Cre mice with HIF-1αflox/flox mice (SM22α-HIF-1α-/-), determined SM-22α-expressing cell identity using single-cell RNA sequencing, and interrogated samples from preterm infants. Deletion of HIF-1α in SM22α-expressing cells had no effect on lung structure at day 3 of life. However, at 8 days, there were fewer and larger alveoli, a difference that persisted into adulthood. Microvascular density, elastin organization, and peripheral branching of the lung vasculature were decreased in SM22α-HIF-1α-/- mice, compared with control mice. Single-cell RNA sequencing demonstrated that three mesenchymal cell subtypes express SM22α: myofibroblasts, airway smooth muscle cells, and vascular smooth muscle cells. Pulmonary vascular smooth muscle cells from SM22α-HIF-1α-/- mice had decreased angiopoietin-2 expression and, in coculture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoietin-2. Angiopoietin-2 expression in tracheal aspirates of preterm infants was inversely correlated with overall mechanical ventilation time, a marker of disease severity. We conclude that SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoietin-2 expression.
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Affiliation(s)
- Elizabeth A. Barnes
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
| | - Carsten Knutsen
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Alida Kindt
- Metabolomics and Analytics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands; and
| | - Xibing Che
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
| | - Lihua Ying
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
| | - Eloa Adams
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
| | - Erika Gonzalez
- Comprehensive Pneumology Center, Ludwig Maximilian University of Munich, Munich, Germany
| | - Prajakta Oak
- Comprehensive Pneumology Center, Ludwig Maximilian University of Munich, Munich, Germany
| | - Anne Hilgendorff
- Comprehensive Pneumology Center, Ludwig Maximilian University of Munich, Munich, Germany
| | - Cristina M. Alvira
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - David N. Cornfield
- Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and
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11
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Hu Y, Zhao Y, Li P, Lu H, Li H, Ge J. Hypoxia and panvascular diseases: exploring the role of hypoxia-inducible factors in vascular smooth muscle cells under panvascular pathologies. Sci Bull (Beijing) 2023; 68:1954-1974. [PMID: 37541793 DOI: 10.1016/j.scib.2023.07.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 08/06/2023]
Abstract
As an emerging discipline, panvascular diseases are a set of vascular diseases with atherosclerosis as the common pathogenic hallmark, which mostly affect vital organs like the heart, brain, kidney, and limbs. As the major responser to the most common stressor in the vasculature (hypoxia)-hypoxia-inducible factors (HIFs), and the primary regulator of pressure and oxygen delivery in the vasculature-vascular smooth muscle cells (VSMCs), their own multifaceted nature and their interactions with each other are fascinating. Abnormally active VSMCs (e.g., atherosclerosis, pulmonary hypertension) or abnormally dysfunctional VSMCs (e.g., aneurysms, vascular calcification) are associated with HIFs. These widespread systemic diseases also reflect the interdisciplinary nature of panvascular medicine. Moreover, given the comparable proliferative characteristics exhibited by VSMCs and cancer cells, and the delicate equilibrium between angiogenesis and cancer progression, there is a pressing need for more accurate modulation targets or combination approaches to bolster the effectiveness of HIF targeting therapies. Based on the aforementioned content, this review primarily focused on the significance of integrating the overall and local perspectives, as well as temporal and spatial balance, in the context of the HIF signaling pathway in VSMC-related panvascular diseases. Furthermore, the review discussed the implications of HIF-targeting drugs on panvascular disorders, while considering the trade-offs involved.
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Affiliation(s)
- Yiqing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Yongchao Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Peng Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Hao Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| | - Hua Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China.
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12
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Kasahara T, Ogata T, Nakanishi N, Tomita S, Higuchi Y, Maruyama N, Hamaoka T, Matoba S. Cavin-2 loss exacerbates hypoxia-induced pulmonary hypertension with excessive eNOS phosphorylation and protein nitration. Heliyon 2023; 9:e17193. [PMID: 37360100 PMCID: PMC10285171 DOI: 10.1016/j.heliyon.2023.e17193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
Pulmonary hypertension (PH) is associated with a poor prognosis even in recent years. Caveolin-1 (CAV1), a caveolae-associated protein, is a causal gene in PH. Cavin-2, one of the other caveolae-associated proteins, forms protein complexes with CAV1 and influences each other's functions. However, the role of Cavin-2 in PH has not been thoroughly investigated. To clarify the role of Cavin-2 in PH, we exposed Cavin-2-deficient (Cavin-2 KO) mice to hypoxia. A part of the analyses was confirmed in human pulmonary endothelial cells (HPAECs). After 4-week 10% O2 hypoxic exposure, we performed physiological, histological, and immunoblotting analyses. Right ventricular (RV) systolic pressure elevation and RV hypertrophy were exacerbated in Cavin-2 KO mice with hypoxia-induced PH (Cavin-2 KO PH mice). The vascular wall thickness of pulmonary arterioles was aggravated in Cavin-2 KO PH mice. Cavin-2 loss reduced CAV1 and induced sustained endothelial nitric oxide synthase (eNOS) hyperphosphorylation in the Cavin-2 KO PH lungs and HPAECs. NOx production associated with eNOS phosphorylation was also increased in the Cavin-2 KO PH lung and HPAECs. Furthermore, the nitration of proteins, including protein kinase G (PKG), was raised in the Cavin-2 KO PH lungs. In conclusion, we revealed that Cavin-2 loss exacerbated hypoxia-induced PH. Our results suggest that Cavin-2 loss leads to sustained eNOS hyperphosphorylation in pulmonary artery endothelial cells via CAV1 reduction, resulting in Nox overproduction-mediated nitration of proteins, including PKG, in smooth muscle cells.
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Affiliation(s)
- Takeru Kasahara
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takehiro Ogata
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Department of Pathology and Cell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Naohiko Nakanishi
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shinya Tomita
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yusuke Higuchi
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Naoki Maruyama
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tetsuro Hamaoka
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Wu XH, He YY, Chen ZR, He ZY, Yan Y, He Y, Wang GM, Dong Y, Yang Y, Sun YM, Ren YH, Zhao QY, Yang XD, Wang LY, Fu CJ, He M, Zhang SJ, Fu JF, Liu H, Jing ZC. Single-cell analysis of peripheral blood from high-altitude pulmonary hypertension patients identifies a distinct monocyte phenotype. Nat Commun 2023; 14:1820. [PMID: 37002243 PMCID: PMC10066231 DOI: 10.1038/s41467-023-37527-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
Immune and inflammatory responses have an important function in the pathophysiology of pulmonary hypertension (PH). However, little is known about the immune landscape in peripheral circulation in patients with high-altitude pulmonary hypertension (HAPH). We apply single-cell transcriptomics to characterize the monocytes that are significantly enriched in the peripheral blood mononuclear cells (PBMC) of HAPH patients. We discover an increase in C1 (non-classical) and C2 (intermediate) monocytes in PBMCs and a decrease in hypoxia-inducible transcription factor-1α (HIF-1α) in all monocyte subsets associated with HAPH. In addition, we demonstrate that similar immune adaptations may exist in HAPH and PH. Overall, we characterize an immune cell atlas of the peripheral blood in HAPH patients. Our data provide evidence that specific monocyte subsets and HIF-1α downregulation might be implicated in the pathogenesis of HAPH.
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Affiliation(s)
- Xin-Hua Wu
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Yang-Yang He
- School of Pharmacy, Henan University, Henan, China
| | - Zhang-Rong Chen
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
- Department of Cardiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Ze-Yuan He
- Department of Cardiology, Yulong People's Hospital, Yunnan, China
| | - Yi Yan
- Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangzhige He
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Guang-Ming Wang
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Yu Dong
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Ying Yang
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Yi-Min Sun
- CapitalBio Technology Corporation, Beijing, China
| | | | - Qiu-Yan Zhao
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Xiao-Dan Yang
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Li-Ying Wang
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Cai-Jun Fu
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Miao He
- Institute of Pharmacy, Dali University, Yunnan, China
| | - Si-Jin Zhang
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji-Fen Fu
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China
| | - Hong Liu
- Department of Cardiology; Yunnan Provincial Engineering Research Center of Prevention and Treatment of Trans-plateau Cardiovascular Diseases, The First Affiliated Hospital of Dali University, Yunnan, China.
| | - Zhi-Cheng Jing
- Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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14
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Loh KWZ, Hu Z, Soong TW. Modulation of Ca V1.2 Channel Function by Interacting Proteins and Post-Translational Modifications: Implications in Cardiovascular Diseases and COVID-19. Handb Exp Pharmacol 2023. [PMID: 36764970 DOI: 10.1007/164_2023_636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
CaV1.2 calcium channel is the primary conduit for Ca2+ influx into cardiac and smooth muscles that underscores its importance in the pathogenesis of hypertension, atherosclerosis, myocardial infarction, and heart failure. But, a few controversies still remain. Therefore, exploring new ways to modulate CaV1.2 channel activity will augment the arsenal of CaV1.2 channel-based therapeutics for treatment of cardiovascular diseases. Here, we will mainly introduce a couple of emerging CaV1.2 channel interacting proteins, such as Galectin-1 and Cereblon, and discuss their roles in hypertension and heart failure through fine-tuning CaV1.2 channel activity. Of current interest, we will also evaluate the implication of the role of CaV1.2 channel in SARS-CoV-2 infection and the potential treatments of COVID-19-related cardiovascular symptoms.
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Affiliation(s)
- Kelvin Wei Zhern Loh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore
| | - Zhenyu Hu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore
| | - Tuck Wah Soong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore. .,Healthy Longevity Translational Research Programme, National University of Singapore, Singapore, Singapore.
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15
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Mitochondrial Regulation of the Hypoxia-Inducible Factor in the Development of Pulmonary Hypertension. J Clin Med 2022; 11:jcm11175219. [PMID: 36079149 PMCID: PMC9457092 DOI: 10.3390/jcm11175219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary hypertension (PH) is a severe progressive lung disorder characterized by pulmonary vasoconstriction and vascular remodeling, culminating in right-sided heart failure and increased mortality. Data from animal models and human subjects demonstrated that hypoxia-inducible factor (HIF)-related signaling is essential in the progression of PH. This review summarizes the regulatory pathways and mechanisms of HIF-mediated signaling, emphasizing the role of mitochondria in HIF regulation and PH pathogenesis. We also try to determine the potential to therapeutically target the components of the HIF system for the management of PH.
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16
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Ito R, Barnes EA, Che X, Alvira CM, Cornfield DN. SM22α cell-specific HIF stabilization mitigates hyperoxia-induced neonatal lung injury. Am J Physiol Lung Cell Mol Physiol 2022; 323:L129-L141. [PMID: 35762602 PMCID: PMC9342196 DOI: 10.1152/ajplung.00110.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Though survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically, BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIFs) may be protective in the context of hyperoxia-induced lung injury, but the cell-specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22α-expressing cells can limit hyperoxia-induced neonatal lung injury. We generated SM22α-specific HIF-1α-stabilized mice (SM22α-PHD1/2-/- mice) by cross-breeding SM22α-promotor-driven Cre recombinase mice with prolyl hydroxylase PHD1flox/flox and PHD2flox/flox mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22α-specific HIF-1α stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In SM22α-PHD1/2-/- mice, pulmonary artery endothelial cells (PAECs) were more proliferative and pulmonary arteries expressed more collagen IV compared with control mice, even under hyperoxic conditions. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in SM22α-PHD1/2-/- compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from SM22α-PHD1/2-/- mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from SM22α-PHD1/2+/+ mice. Addition of Ang2 recombinant protein further augmented tube formation for both PHD1/2+/+ and PHD1/2-/- PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1α expression in SM22α-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22α-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1α stabilization to prevent neonatal lung injury.
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Affiliation(s)
- Reiji Ito
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California
| | - Elizabeth A. Barnes
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California
| | - Xibing Che
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California
| | - Cristina M. Alvira
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California
| | - David N. Cornfield
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California
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17
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Yu B, Wang X, Song Y, Xie G, Jiao S, Shi L, Cao X, Han X, Qu A. The role of hypoxia-inducible factors in cardiovascular diseases. Pharmacol Ther 2022; 238:108186. [PMID: 35413308 DOI: 10.1016/j.pharmthera.2022.108186] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/29/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. During the development of cardiovascular diseases, hypoxia plays a crucial role. Hypoxia-inducible factors (HIFs) are the key transcription factors for adaptive hypoxic responses, which orchestrate the transcription of numerous genes involved in angiogenesis, erythropoiesis, glycolytic metabolism, inflammation, and so on. Recent studies have dissected the precise role of cell-specific HIFs in the pathogenesis of hypertension, atherosclerosis, aortic aneurysms, pulmonary arterial hypertension, and heart failure using tissue-specific HIF-knockout or -overexpressing animal models. More importantly, several compounds developed as HIF inhibitors or activators have been in clinical trials for the treatment of renal cancer or anemia; however, little is known on the therapeutic potential of these inhibitors for cardiovascular diseases. The purpose of this review is to summarize the recent advances on HIFs in the pathogenesis and pathophysiology of cardiovascular diseases and to provide evidence of potential clinical therapeutic targets.
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Affiliation(s)
- Baoqi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xia Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Yanting Song
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China; Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Shiyu Jiao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Li Shi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xuejie Cao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xinyao Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China.
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18
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Durgin BG, Wood KC, Hahn SA, McMahon B, Baust JJ, Straub AC. Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress. J Mol Cell Cardiol 2022; 162:72-80. [PMID: 34536439 PMCID: PMC8766905 DOI: 10.1016/j.yjmcc.2021.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 01/03/2023]
Abstract
Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe2+) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation. Under chronic hypoxia, oxidative stress drives oxidation of sGC heme (Fe2+→Fe3+), rendering it NO-insensitive. We previously showed that cytochrome b5 reductase 3 (CYB5R3) in SMC is a sGC reductase important for maintaining NO-dependent vasodilation and conferring resilience to systemic hypertension and sickle cell disease-associated pulmonary hypertension. To test whether CYB5R3 may be protective in the context of chronic hypoxia, we subjected SMC-specific CYB5R3 knockout mice (SMC CYB5R3 KO) to 3 weeks hypoxia and assessed vascular and cardiac function using echocardiography, pressure volume loops and wire myography. Hypoxic stress caused 1) biventricular hypertrophy in both WT and SMC CYB5R3 KO, but to a larger degree in KO mice, 2) blunted vasodilation to NO-dependent activation of sGC in coronary and pulmonary arteries of KO mice, and 3) decreased, albeit still normal, cardiac function in KO mice. Overall, these data indicate that SMC CYB5R3 deficiency potentiates bilateral ventricular hypertrophy and blunts NO-dependent vasodilation under chronic hypoxia conditions. This implicates that SMC CYB5R3 KO mice post 3-week hypoxia have early stages of cardiac remodeling and functional changes that could foretell significantly impaired cardiac function with longer exposure to hypoxia.
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Affiliation(s)
- Brittany G Durgin
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Katherine C Wood
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Scott A Hahn
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Brenda McMahon
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Jeffrey J Baust
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Adam C Straub
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States of America; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, PA, United States of America.
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Zhu J, Zhao L, Hu Y, Cui G, Luo A, Bao C, Han Y, Zhou T, Lu W, Wang J, Black SM, Tang H. Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension. Front Cell Dev Biol 2021; 9:701247. [PMID: 34422822 PMCID: PMC8375387 DOI: 10.3389/fcell.2021.701247] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/16/2021] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVES HIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects. METHODS Using transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments. RESULTS 19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 EC-/- mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis. CONCLUSION HIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.
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Affiliation(s)
- Jinsheng Zhu
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Li Zhao
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Yadan Hu
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Guoqi Cui
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Ang Luo
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Changlei Bao
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Ying Han
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Tong Zhou
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, United States
| | - Wenju Lu
- State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Stephen M. Black
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Miami, FL, United States
- Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, FL, United States
- Center for Translational Science, Florida International University, Port St. Lucie, FL, United States
| | - Haiyang Tang
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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20
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Shimoda LA. Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia. Physiology (Bethesda) 2021; 35:222-233. [PMID: 32490752 DOI: 10.1152/physiol.00039.2019] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Exposure to hypoxia increases pulmonary vascular resistance, leading to elevated pulmonary arterial pressure and, potentially, right heart failure. Vascular remodeling is an important contributor to the increased pulmonary vascular resistance. Hyperproliferation of smooth muscle, endothelial cells, and fibroblasts, and deposition of extracellular matrix lead to increased wall thickness, extension of muscle into normally non-muscular arterioles, and vascular stiffening. This review highlights intrinsic and extrinsic modulators contributing to the remodeling process.
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Affiliation(s)
- Larissa A Shimoda
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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21
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Pullamsetti SS, Mamazhakypov A, Weissmann N, Seeger W, Savai R. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest 2021; 130:5638-5651. [PMID: 32881714 DOI: 10.1172/jci137558] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.
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Affiliation(s)
- Soni Savai Pullamsetti
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.,Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL and CPI, Justus Liebig University, Giessen, Germany
| | - Argen Mamazhakypov
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Norbert Weissmann
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL and CPI, Justus Liebig University, Giessen, Germany
| | - Werner Seeger
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.,Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL and CPI, Justus Liebig University, Giessen, Germany.,Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
| | - Rajkumar Savai
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.,Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL and CPI, Justus Liebig University, Giessen, Germany.,Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.,Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany
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22
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Hirsch K, Taglauer E, Seedorf G, Callahan C, Mandell E, White CW, Kourembanas S, Abman SH. Perinatal Hypoxia-Inducible Factor Stabilization Preserves Lung Alveolar and Vascular Growth in Experimental Bronchopulmonary Dysplasia. Am J Respir Crit Care Med 2020; 202:1146-1158. [PMID: 32551816 PMCID: PMC7560790 DOI: 10.1164/rccm.202003-0601oc] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Rationale: Antenatal inflammation with placental dysfunction is strongly associated with high bronchopulmonary dysplasia (BPD) risk in preterm infants. Whether antenatal or postnatal HIF (hypoxia-inducible factor) augmentation can preserve lung structure and function and prevent pulmonary hypertension after intrauterine inflammation is controversial.Objectives: To determine whether antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function, and prevents pulmonary hypertension in a rat model of chorioamnionitis-induced BPD caused by antenatal inflammation.Methods: Endotoxin (ETX) was administered to pregnant rats by intraamniotic injection at Embryonic Day 20, and pups were delivered by cesarean section at Embryonic Day 22. Selective PHi drugs, dimethyloxalylglycine or GSK360A, were administered into the amniotic space at Embryonic Day 20 or after birth by intraperitoneal injection for 2 weeks. Placentas and lung tissue were collected at birth for morphometric and Western blot measurements of HIF-1a, HIF-2a, VEGF (vascular endothelial growth factor), and eNOS (endothelial nitric oxide synthase) protein contents. At Day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts, pulmonary vessel density, and right ventricle hypertrophy (RVH).Measurements and Main Results: Antenatal PHi therapy preserves lung alveolar and vascular growth and lung function and prevents RVH after intrauterine ETX exposure. Antenatal administration of PHi markedly upregulates lung HIF-1a, HIF-2a, VEGF, and eNOS expression after ETX exposure.Conclusions: HIF augmentation improves lung structure and function, prevents RVH, and improves placental structure following antenatal ETX exposure. We speculate that antenatal or postnatal PHi therapy may provide novel strategies to prevent BPD due to antenatal inflammation.
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Affiliation(s)
- Kellen Hirsch
- Pediatric Heart Lung Center and,Medical Student Research Track, School of Medicine, and
| | - Elizabeth Taglauer
- Division of Neonatology, Boston Children’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts; and
| | - Gregory Seedorf
- Pediatric Heart Lung Center and,Pediatric Pulmonology Clinic, Children’s Hospital Colorado, Aurora, Colorado,Department of Pediatrics, Anschutz Medical Center, University of Colorado Denver, Aurora, Colorado
| | - Carly Callahan
- University of Southern California, Los Angeles, California
| | | | - Carl W. White
- Pediatric Pulmonology Clinic, Children’s Hospital Colorado, Aurora, Colorado,Department of Pediatrics, Anschutz Medical Center, University of Colorado Denver, Aurora, Colorado
| | - Stella Kourembanas
- Division of Neonatology, Boston Children’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts; and
| | - Steven H. Abman
- Pediatric Heart Lung Center and,Pediatric Pulmonology Clinic, Children’s Hospital Colorado, Aurora, Colorado,Department of Pediatrics, Anschutz Medical Center, University of Colorado Denver, Aurora, Colorado
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23
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Nozik-Grayck E, Shimoda LA. Heart of the Matter: Divergent Roles of Hypoxia-Inducible Factors in Hypoxia-induced Right Ventricle Hypertrophy. Am J Respir Cell Mol Biol 2020; 63:549-550. [PMID: 32790477 PMCID: PMC7605162 DOI: 10.1165/rcmb.2020-0325ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Eva Nozik-Grayck
- Department of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado and
| | - Larissa A Shimoda
- Department of Medicine, John Hopkins Medical Institution, Baltimore, Maryland
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24
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Hu CJ, Poth JM, Zhang H, Flockton A, Laux A, Kumar S, McKeon B, Mouradian G, Li M, Riddle S, Pugliese SC, Brown RD, Wallace EM, Graham BB, Frid MG, Stenmark KR. Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension. Eur Respir J 2019; 54:13993003.00378-2019. [PMID: 31515405 DOI: 10.1183/13993003.00378-2019] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 08/28/2019] [Indexed: 11/05/2022]
Abstract
Most published studies addressing the role of hypoxia inducible factors (HIFs) in hypoxia-induced pulmonary hypertension development employ models that may not recapitulate the clinical setting, including the use of animals with pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Furthermore, critical questions including how and when HIF signalling contributes to hypoxia-induced pulmonary hypertension remain unanswered.Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4-5 weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion).Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5 weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2-ASO (but not Hif1-ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4-5 weeks of hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia. In vitro, HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice.Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal.
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Affiliation(s)
- Cheng-Jun Hu
- Dept of Craniofacial Biology, School of Dental Medicine, University of Colorado, Aurora, CO, USA.,Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA.,These authors share first authorship.,These authors are joint corresponding authors
| | - Jens M Poth
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA.,Dept of Anesthesiology and Intensive Care Medicine, University Medical Center, Rheinische Friedrich Wilhelms University of Bonn, Bonn, Germany.,These authors share first authorship
| | - Hui Zhang
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Amanda Flockton
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Aya Laux
- Dept of Craniofacial Biology, School of Dental Medicine, University of Colorado, Aurora, CO, USA
| | - Sushil Kumar
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Brittany McKeon
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Gary Mouradian
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Min Li
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Suzette Riddle
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Steven C Pugliese
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - R Dale Brown
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | | | - Brian B Graham
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Maria G Frid
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Kurt R Stenmark
- Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA .,These authors are joint corresponding authors
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25
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Waypa GB, Schumacker PT. Roles of HIF1 and HIF2 in pulmonary hypertension: it all depends on the context. Eur Respir J 2019; 54:54/6/1901929. [PMID: 31831673 DOI: 10.1183/13993003.01929-2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/30/2019] [Indexed: 01/23/2023]
Affiliation(s)
- Gregory B Waypa
- Dept of Pediatrics, Northwestern University Feinberg School of Medicine, Anne and Robert H. Lurie Children's Hospital, Chicago, IL, USA
| | - Paul T Schumacker
- Dept of Pediatrics, Northwestern University Feinberg School of Medicine, Anne and Robert H. Lurie Children's Hospital, Chicago, IL, USA
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26
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Hu Z, Li G, Wang JW, Chong SY, Yu D, Wang X, Soon JL, Liang MC, Wong YP, Huang N, Colecraft HM, Liao P, Soong TW. Regulation of Blood Pressure by Targeting Ca V1.2-Galectin-1 Protein Interaction. Circulation 2019; 138:1431-1445. [PMID: 29650545 DOI: 10.1161/circulationaha.117.031231] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND L-type CaV1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current density. However, the mechanistic understanding for the downregulation of CaV1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. METHODS In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates CaV1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from Lgasl1-/- mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods. RESULTS Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with the CaVβ subunit for binding to the I-II loop of the CaV1.2 channel. This competitive disruption of CaVβ binding led to CaV1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats. CONCLUSIONS We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVβ and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.
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Affiliation(s)
- Zhenyu Hu
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore
| | - Guang Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China (G.L.)
| | - Jiong-Wei Wang
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore.,Department of Surgery, Yong Loo Lin School of Medicine (J.-W.W., S.Y.C., X.W.), National University of Singapore.,Cardiovascular Research Institute, National University Heart Center, National University Health Systems, Centre for Translational Medicine, Singapore (J.-W.W., S.Y.C., X.W.)
| | - Suet Yen Chong
- Department of Surgery, Yong Loo Lin School of Medicine (J.-W.W., S.Y.C., X.W.), National University of Singapore.,Cardiovascular Research Institute, National University Heart Center, National University Health Systems, Centre for Translational Medicine, Singapore (J.-W.W., S.Y.C., X.W.)
| | - Dejie Yu
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore
| | - Xiaoyuan Wang
- Department of Surgery, Yong Loo Lin School of Medicine (J.-W.W., S.Y.C., X.W.), National University of Singapore.,Cardiovascular Research Institute, National University Heart Center, National University Health Systems, Centre for Translational Medicine, Singapore (J.-W.W., S.Y.C., X.W.)
| | | | - Mui Cheng Liang
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore
| | - Yuk Peng Wong
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore
| | - Na Huang
- National Heart Centre Singapore (J.L.S., N.H.)
| | - Henry M Colecraft
- Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York (H.M.C.)
| | | | - Tuck Wah Soong
- Department of Physiology, Yong Loo Lin School of Medicine (Z.Y.H., J.-W.W., D.Y., M.C.L., Y.P.W., T.W.S.), National University of Singapore.,Neurobiology/Ageing Programme (T.W.S.), National University of Singapore.,Graduate School for Integrative Sciences and Engineering (T.W.S.), National University of Singapore.,National Neuroscience Institute, Singapore (T.W.S.)
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27
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Spiekerkoetter E, Goncharova EA, Guignabert C, Stenmark K, Kwapiszewska G, Rabinovitch M, Voelkel N, Bogaard HJ, Graham B, Pullamsetti SS, Kuebler WM. Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure. Pulm Circ 2019; 9:2045894019889775. [PMID: 31798835 PMCID: PMC6868582 DOI: 10.1177/2045894019889775] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023] Open
Abstract
In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.
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Affiliation(s)
- Edda Spiekerkoetter
- Division of Pulmonary and Critical Care Medicine, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Elena A. Goncharova
- Pittsburgh Heart, Blood and Vascular Medicine Institute, Pulmonary, Allergy & Critical Care Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Christophe Guignabert
- INSERM UMR_S 999, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Kurt Stenmark
- Department of Pediatrics, School of Medicine, University of Colorado, Denver, CO, USA
- Cardio Vascular Pulmonary Research Lab, University of Colorado, Denver, CO, USA
| | - Grazyna Kwapiszewska
- Ludwig Boltzmann Institute, Lung Vascular Research, Medical University of Graz, Graz, Austria
| | - Marlene Rabinovitch
- Division of Pediatric Cardiology, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Norbert Voelkel
- Department of Pulmonary Medicine, Vrije Universiteit MC, Amsterdam, The Netherlands
| | - Harm J. Bogaard
- Department of Pulmonary Medicine, Vrije Universiteit MC, Amsterdam, The Netherlands
| | - Brian Graham
- Pulmonary Sciences and Critical Care, School of Medicine, University of Colorado, Denver, CO, USA
| | - Soni S. Pullamsetti
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
| | - Wolfgang M. Kuebler
- Institute of Physiology, Charité – Universitaetsmedizin Berlin, Berlin, Germany
- The Keenan Research Centre for Biomedical Science at St. Michael's, Toronto, ON, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
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28
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Sheikh AQ, Saddouk FZ, Ntokou A, Mazurek R, Greif DM. Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension. Cell Rep 2019; 23:1152-1165. [PMID: 29694892 PMCID: PMC5959296 DOI: 10.1016/j.celrep.2018.03.043] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 02/26/2018] [Accepted: 03/11/2018] [Indexed: 02/08/2023] Open
Abstract
Pulmonary hypertension is a devastating disease characterized by excessive vascular muscularization. We previously demonstrated primed platelet-derived growth factor receptor β+ (PDGFR-β+)/smooth muscle cell (SMC) marker+ progenitors at the muscular-unmuscular arteriole border in the normal lung, and in hypoxia-induced pulmonary hypertension, a single primed cell migrates distally and expands clonally, giving rise to most of the pathological smooth muscle coating of small arterioles. Little is known regarding the molecular mechanisms underlying this process. Herein, we show that primed cell expression of Kruppel-like factor 4 and hypoxia-inducible factor 1-α(HIF1-α) are required, respectively, for distal migration and smooth muscle expansion in a sequential manner. In addition, the HIF1-α/PDGF-B axis in endothelial cells non-cell autonomously regulates primed cell induction, proliferation, and differentiation. Finally, myeloid cells transdifferentiate into or fuse with distal arteriole SMCs during hypoxia, and Pdgfb deletion in myeloid cells attenuates pathological muscularization. Thus, primed cell autonomous and non-cell autonomous pathways are attractive therapeutic targets for pulmonary hypertension.
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Affiliation(s)
- Abdul Q Sheikh
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Fatima Zahra Saddouk
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Aglaia Ntokou
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Renata Mazurek
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Daniel M Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, USA.
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Young JM, Williams DR, Thompson AAR. Thin Air, Thick Vessels: Historical and Current Perspectives on Hypoxic Pulmonary Hypertension. Front Med (Lausanne) 2019; 6:93. [PMID: 31119132 PMCID: PMC6504829 DOI: 10.3389/fmed.2019.00093] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/16/2019] [Indexed: 12/21/2022] Open
Abstract
The association between pulmonary hypertension (PH) and hypoxia is well-established, with two key mechanistic processes, hypoxic pulmonary vasoconstriction and hypoxia-induced vascular remodeling, driving changes in pulmonary arterial pressure. In contrast to other forms of pulmonary hypertension, the vascular changes induced by hypoxia are reversible, both in humans returning to sea-level from high altitude and in animal models. This raises the intriguing possibility that the molecular drivers of these hypoxic processes could be targeted to modify pulmonary vascular remodeling in other contexts. In this review, we outline the history of research into PH and hypoxia, before discussing recent advances in our understanding of this relationship at the molecular level, focussing on the role of the oxygen-sensing transcription factors, hypoxia inducible factors (HIFs). Emerging links between HIF and vascular remodeling highlight the potential utility in inhibiting this pathway in pulmonary hypertension and raise possible risks of activating this pathway using HIF-stabilizing medications.
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Affiliation(s)
- Jason M. Young
- Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
- Apex (Altitude Physiology Expeditions), Edinburgh, United Kingdom
| | | | - A. A. Roger Thompson
- Apex (Altitude Physiology Expeditions), Edinburgh, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
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30
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Shimoda LA, Yun X, Sikka G. Revisiting the role of hypoxia-inducible factors in pulmonary hypertension. CURRENT OPINION IN PHYSIOLOGY 2019; 7:33-40. [PMID: 33103021 DOI: 10.1016/j.cophys.2018.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary hypertension (PH) is a deadly condition with limited treatment options. Early studies implicated hypoxia-inducible factors as contributing to the development of hypoxia-induced PH. Recently, the use of cells derived from patients and transgenic animals with cell specific deletions for various parts of the HIF system have furthered our understanding of the mechanisms by which HIFs control pulmonary vascular tone and remodeling to promote PH. Additionally, identification of HIF inhibitors further allows assessment of the potential for targeting HIFs to prevent and/or reverse PH. In this review, recent findings exploring the role of HIFs as potential mediators and therapeutic targets for PH are discussed.
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Affiliation(s)
- Larissa A Shimoda
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224
| | - Xin Yun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224
| | - Gautam Sikka
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224
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31
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Sallis BF, Acar U, Hawthorne K, Babcock SJ, Kanagaratham C, Goldsmith JD, Rosen R, Vanderhoof JA, Nurko S, Fiebiger E. A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions. Front Immunol 2018; 9:2059. [PMID: 30455683 PMCID: PMC6230678 DOI: 10.3389/fimmu.2018.02059] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/21/2018] [Indexed: 12/17/2022] Open
Abstract
Eosinophilic esophagitis (EoE), a Th2-type allergic immune disorder characterized by an eosinophil-rich esophageal immune infiltrate, is often associated with food impaction (FI) in pediatric patients but the molecular mechanisms underlying the development of this complication are not well understood. We aim to identify molecular pathways involved in the development of FI. Due to large variations in disease presentation, our analysis was further geared to find markers capable of distinguishing EoE patients that are prone to develop food impactions and thus expand an established medical algorithm for EoE by developing a secondary analysis that allows for the identification of patients with food impactions as a distinct patient population. To this end, mRNA patterns from esophageal biopsies of pediatric EoE patients presenting with and without food impactions were compared and machine learning techniques were employed to establish a diagnostic probability score to identify patients with food impactions (EoE+FI). Our analysis showed that EoE patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based p(EoE). Irrespectively, an additional analysis loop of the medical algorithm was able to separate EoE+FI patients and a composite FI-score was established that identified such patients with a sensitivity of 93% and a specificity of 100%. The esophageal mRNA pattern of EoE+FI patients was typified by lower expression levels of mast cell markers and Th2 associated transcripts, such as FCERIB, CPA3, CCL2, IL4, and IL5. Furthermore, lower expression levels of regulators of esophageal motility (NOS2 and HIF1A) were detected in EoE+FI. The EoE+FI -specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients. The availability of improved diagnostic tools such as a medical algorithm for EoE subpopulations will have a direct impact on clinical practice because such strategies can identify molecular inflammatory characteristics of individual EoE patients, which, in turn, will facilitate the development of individualized therapeutic approaches that target the relevant pathways affected in each patient.
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Affiliation(s)
- Benjamin F. Sallis
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
| | - Utkucan Acar
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
| | - Kelsey Hawthorne
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
- Center for Motility and Functional Gastrointestinal Disorders Boston Children's Hospital, Boston, MA, United States
| | - Stephen J. Babcock
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
| | - Cynthia Kanagaratham
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
| | | | - Rachel Rosen
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
- Center for Motility and Functional Gastrointestinal Disorders Boston Children's Hospital, Boston, MA, United States
- Department of Pathology, Boston Children's Hospital, Boston, MA, United States
| | - Jon A. Vanderhoof
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
| | - Samuel Nurko
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
- Center for Motility and Functional Gastrointestinal Disorders Boston Children's Hospital, Boston, MA, United States
| | - Edda Fiebiger
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States
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32
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Wang Z, Yang K, Zheng Q, Zhang C, Tang H, Babicheva A, Jiang Q, Li M, Chen Y, Carr SG, Wu K, Zhang Q, Balistrieri A, Wang C, Song S, Ayon RJ, Desai AA, Black SM, Garcia JGN, Makino A, Yuan JXJ, Lu W, Wang J. Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2018; 316:L216-L228. [PMID: 30358436 DOI: 10.1152/ajplung.00538.2017] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]cyt). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.
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Affiliation(s)
- Ziyi Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.,Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Kai Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Qiuyu Zheng
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Chenting Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Haiyang Tang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.,Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Aleksandra Babicheva
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Qian Jiang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Meichan Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Yuqin Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Shane G Carr
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Kang Wu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.,Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Qian Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.,Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Department of Physiology, The University of Arizona College of Medicine , Tucson, Arizona
| | - Angela Balistrieri
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Christina Wang
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Shanshan Song
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Ramon J Ayon
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Ankit A Desai
- Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona
| | - Stephen M Black
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Department of Physiology, The University of Arizona College of Medicine , Tucson, Arizona
| | - Joe G N Garcia
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Department of Physiology, The University of Arizona College of Medicine , Tucson, Arizona
| | - Ayako Makino
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Department of Physiology, The University of Arizona College of Medicine , Tucson, Arizona
| | - Jason X-J Yuan
- Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Department of Physiology, The University of Arizona College of Medicine , Tucson, Arizona
| | - Wenju Lu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.,Division of Translational and Regenerative Medicine , Tucson, Arizona.,Department of Medicine, The University of Arizona College of Medicine , Tucson, Arizona.,Division of Pulmonary and Critical Care Medicine, The People's Hospital of Inner Mongolia, Huhhot, Inner Mongolia, China
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33
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34
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Barnes EA, Lee L, Barnes SL, Brenner R, Alvira CM, Cornfield DN. β1-Subunit of the calcium-sensitive potassium channel modulates the pulmonary vascular smooth muscle cell response to hypoxia. Am J Physiol Lung Cell Mol Physiol 2018; 315:L265-L275. [PMID: 29644895 PMCID: PMC6139656 DOI: 10.1152/ajplung.00060.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 11/22/2022] Open
Abstract
Accessory subunits associated with the calcium-sensitive potassium channel (BKCa), a major determinant of vascular tone, confer functional and anatomical diversity. The β1 subunit increases Ca2+ and voltagesensitivity of the BKCa channel and is expressed exclusively in smooth muscle cells. Evidence supporting the physiological significance of the β1 subunit includes the observations that murine models with deletion of the β1 subunit are hypertensive and that humans with a gain-of-function β1 mutation are at a decreased risk of diastolic hypertension. However, whether the β1 subunit of the BKCa channel contributes to the low tone that characterizes the normal pulmonary circulation or modulates the pulmonary vascular response to hypoxia remains unknown. To determine the role of the BKCa channel β1 subunit in the regulation of pulmonary vascular tone and the response to acute and chronic hypoxia, mice with deletion of the Kcnmb1 gene that encodes for the β1 subunit ( Kcnmb1-/-) were placed in chronic hypoxia (10% O2) for 21-24 days. In normoxia, right ventricular systolic pressure (RVSP) did not differ between Kcnmb1+/+ (controls) and Kcnmb1-/- mice. After exposure to either acute or chronic hypoxia, RVSP was higher in Kcnmb1-/- mice compared with Kcnmb1+/+ mice, without increased vascular remodeling. β1 subunit expression was predominantly confined to pulmonary artery smooth muscle cells (PASMCs) from vessels ≤ 150 µm. Peripheral PASMCs contracted collagen gels irrespective of β1 expression. Focal adhesion expression and Rho kinase activity were greater in Kcnmb1-/- compared with Kcnmb1+/+ PASMCs. Compromised PASMC β1 function may contribute to the heightened microvascular vasoconstriction that characterizes pulmonary hypertension.
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MESH Headings
- Acute Disease
- Animals
- Chronic Disease
- Focal Adhesions/genetics
- Focal Adhesions/metabolism
- Focal Adhesions/pathology
- Gene Deletion
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypoxia/genetics
- Hypoxia/metabolism
- Hypoxia/pathology
- Large-Conductance Calcium-Activated Potassium Channel beta Subunits/genetics
- Large-Conductance Calcium-Activated Potassium Channel beta Subunits/metabolism
- Lung/blood supply
- Lung/metabolism
- Lung/pathology
- Mice
- Mice, Knockout
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Vasoconstriction
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Affiliation(s)
- Elizabeth A Barnes
- Division of Pulmonary Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
| | - Lori Lee
- Division of Pulmonary Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
| | - Shayna L Barnes
- Division of Pulmonary Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
| | - Robert Brenner
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Sciences Center , San Antonio, Texas
| | - Cristina M Alvira
- Division of Pulmonary Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
| | - David N Cornfield
- Division of Pulmonary Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine , Stanford, California
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35
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Zhang M, Wu Y, Wang M, Wang Y, Tausif R, Yang Y. Genistein rescues hypoxia-induced pulmonary arterial hypertension through estrogen receptor and β-adrenoceptor signaling. J Nutr Biochem 2018; 58:110-118. [DOI: 10.1016/j.jnutbio.2018.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 04/20/2018] [Accepted: 04/21/2018] [Indexed: 12/29/2022]
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36
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Shen YS, Goncharova EA. TWISTed HIF: revisiting smooth muscle HIF-1α signaling in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2018; 315:L387-L389. [PMID: 29975104 DOI: 10.1152/ajplung.00285.2018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Yuanjun Steven Shen
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Elena A Goncharova
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania.,Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.,Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania
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37
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Urrutia AA, Aragonés J. HIF Oxygen Sensing Pathways in Lung Biology. Biomedicines 2018; 6:biomedicines6020068. [PMID: 29882755 PMCID: PMC6027477 DOI: 10.3390/biomedicines6020068] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 05/28/2018] [Accepted: 05/30/2018] [Indexed: 12/30/2022] Open
Abstract
Cellular responses to oxygen fluctuations are largely mediated by hypoxia-inducible factors (HIFs). Upon inhalation, the first organ inspired oxygen comes into contact with is the lungs, but the understanding of the pulmonary HIF oxygen-sensing pathway is still limited. In this review we will focus on the role of HIF1α and HIF2α isoforms in lung responses to oxygen insufficiency. In particular, we will discuss novel findings regarding their role in the biology of smooth muscle cells and endothelial cells in the context of hypoxia-induced pulmonary vasoconstriction. Moreover, we will also discuss recent studies into HIF-dependent responses in the airway epithelium, which have been even less studied than the HIF-dependent vascular responses in the lungs. In summary, we will review the biological functions executed by HIF1 or HIF2 in the pulmonary vessels and epithelium to control lung responses to oxygen fluctuations as well as their pathological consequences in the hypoxic lung.
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Affiliation(s)
- Andrés A Urrutia
- Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, Spain.
| | - Julián Aragonés
- Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, Carlos III Health Institute, 28029 Madrid, Spain.
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38
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Borton AH, Benson BL, Neilson LE, Saunders A, Alaiti MA, Huang AY, Jain MK, Proweller A, Ramirez-Bergeron DL. Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery. J Am Heart Assoc 2018; 7:e009205. [PMID: 29858371 PMCID: PMC6015385 DOI: 10.1161/jaha.118.009205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/02/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Limb ischemia resulting from peripheral vascular disease is a common cause of morbidity. Vessel occlusion limits blood flow, creating a hypoxic environment that damages distal tissue, requiring therapeutic revascularization. Hypoxia-inducible factors (HIFs) are key transcriptional regulators of hypoxic vascular responses, including angiogenesis and arteriogenesis. Despite vascular smooth muscle cells' (VSMCs') importance in vessel integrity, little is known about their functional responses to hypoxia in peripheral vascular disease. This study investigated the role of VSMC HIF in mediating peripheral ischemic responses. METHODS AND RESULTS We used ArntSMKO mice with smooth muscle-specific deletion of aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β), required for HIF transcriptional activity, in a femoral artery ligation model of peripheral vascular disease. ArntSMKO mice exhibit impaired perfusion recovery despite normal collateral vessel dilation and angiogenic capillary responses. Decreased blood flow manifests in extensive tissue damage and hypoxia in ligated limbs of ArntSMKO mice. Furthermore, loss of aryl hydrocarbon receptor nuclear translocator changes the proliferation, migration, and transcriptional profile of cultured VSMCs. ArntSMKO mice display disrupted VSMC morphologic features and wrapping around arterioles and increased vascular permeability linked to decreased local blood flow. CONCLUSIONS Our data demonstrate that traditional vascular remodeling responses are insufficient to provide robust peripheral tissue reperfusion in ArntSMKO mice. In all, this study highlights HIF responses to hypoxia in arteriole VSMCs critical for the phenotypic and functional stability of vessels that aid in the recovery of blood flow in ischemic peripheral tissues.
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MESH Headings
- Animals
- Aryl Hydrocarbon Receptor Nuclear Translocator/biosynthesis
- Aryl Hydrocarbon Receptor Nuclear Translocator/genetics
- Blotting, Western
- Cells, Cultured
- Disease Models, Animal
- Gene Expression Regulation
- Immunohistochemistry
- Ischemia/genetics
- Ischemia/metabolism
- Ischemia/pathology
- Lower Extremity/blood supply
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Confocal
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Peripheral Vascular Diseases/genetics
- Peripheral Vascular Diseases/metabolism
- Peripheral Vascular Diseases/pathology
- RNA/genetics
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Anna Henry Borton
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
| | - Bryan L Benson
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Lee E Neilson
- Neurological Institute, University Hospitals, Cleveland, OH
| | - Ashley Saunders
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
| | - M Amer Alaiti
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
| | - Alex Y Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
- Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital University Hospitals, Cleveland, OH
| | - Mukesh K Jain
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
| | - Aaron Proweller
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
| | - Diana L Ramirez-Bergeron
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH
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Wang CC, Ying L, Barnes EA, Adams ES, Kim FY, Engel KW, Alvira CM, Cornfield DN. Pulmonary artery smooth muscle cell HIF-1α regulates endothelin expression via microRNA-543. Am J Physiol Lung Cell Mol Physiol 2018; 315:L422-L431. [PMID: 29745253 DOI: 10.1152/ajplung.00475.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Pulmonary artery smooth muscle cells (PASMCs) express endothelin (ET-1), which modulates the pulmonary vascular response to hypoxia. Although cross-talk between hypoxia-inducible factor-1α (HIF-1α), an O2-sensitive transcription factor, and ET-1 is established, the cell-specific relationship between HIF-1α and ET-1 expression remains incompletely understood. We tested the hypotheses that in PASMCs 1) HIF-1α expression constrains ET-1 expression, and 2) a specific microRNA (miRNA) links HIF-1α and ET-1 expression. In human (h)PASMCs, depletion of HIF-1α with siRNA increased ET-1 expression at both the mRNA and protein levels ( P < 0.01). In HIF-1α-/- murine PASMCs, ET-1 gene and protein expression was increased ( P < 0.0001) compared with HIF-1α+/+ cells. miRNA profiles were screened in hPASMCs transfected with siRNA-HIF-1α, and RNA hybridization was performed on the Agilent (Santa Clara, CA) human miRNA microarray. With HIF-1α depletion, miRNA-543 increased 2.4-fold ( P < 0.01). In hPASMCs, miRNA-543 overexpression increased ET-1 gene ( P < 0.01) and protein ( P < 0.01) expression, decreased TWIST gene expression ( P < 0.05), and increased ET-1 gene and protein expression, compared with nontargeting controls ( P < 0.01). Moreover, we evaluated low passage hPASMCs from control and patients with idiopathic pulmonary arterial hypertension (IPAH). Compared with controls, protein expression of HIF-1α and Twist-related protein-1 (TWIST1) was decreased ( P < 0.05), and miRNA-543 and ET-1 expression increased ( P < 0.001) in hPASMCs from patients with IPAH. Thus, in PASMCs, loss of HIF-1α increases miRNA-543, which decreases Twist expression, leading to an increase in PASMC ET-1 expression. This previously undescribed link between HIF-1α and ET-1 via miRNA-543 mediated Twist suppression represents another layer of molecular regulation that might determine pulmonary vascular tone.
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Affiliation(s)
- Ching-Chia Wang
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University Medical College , Taipei , Taiwan
| | - Lihua Ying
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School , Stanford, California
| | - Elizabeth A Barnes
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School , Stanford, California
| | - Eloa S Adams
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Kaiser Oakland, Oakland, California
| | - Francis Y Kim
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Milwaukee Children's Hospital, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Karl W Engel
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California
| | - Cristina M Alvira
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Division of Critical Care Medicine, Department of Pediatrics, Stanford University Medical School , Stanford, California
| | - David N Cornfield
- Center for Excellence in Pulmonary Biology, Stanford University Medical School , Stanford, California.,Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School , Stanford, California.,Division of Critical Care Medicine, Department of Pediatrics, Stanford University Medical School , Stanford, California
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40
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Chen T, Zhou Q, Tang H, Bozkanat M, Yuan JXJ, Raj JU, Zhou G. miR-17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia-Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation. J Am Heart Assoc 2016; 5:e004510. [PMID: 27919930 PMCID: PMC5210422 DOI: 10.1161/jaha.116.004510] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 11/08/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Previously we found that smooth muscle cell (SMC)-specific knockout of miR-17~92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17~92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17~92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). METHODS AND RESULTS We show that hypoxic sm-17~92-/- mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm-17~92-/- mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR-17~92 inhibitors suppress hypoxia-induced levels of HIF1α, VEGF, Glut1, HK2, and PDK1 but not HIF2α in vitro in PASMC. Overexpression of miR-17 in PASMC represses PHD2 expression, whereas miR-17/20a inhibitors induce PHD2 expression. The 3'-UTR of PHD2 contains a functional miR-17/20a seed sequence. Silencing of PHD2 induces HIF1α and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1α and cell proliferation. SMC-specific knockout of PHD2 enhances hypoxia-induced vascular remodeling and exacerbates established pulmonary hypertension in mice. PHD2 activator R59949 reverses vessel remodeling in existing hypertensive mice. PHDs are dysregulated in PASMC isolated from pulmonary arterial hypertension patients. CONCLUSIONS Our results suggest that PHD2 is a direct target of miR-17/20a and that miR-17~92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1α.
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Affiliation(s)
- Tianji Chen
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL
| | - Qiyuan Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL
| | - Haiyang Tang
- Department of Medicine, University of Arizona, Tucson, AZ
| | - Melike Bozkanat
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL
| | - Jason X-J Yuan
- Department of Medicine, University of Arizona, Tucson, AZ
| | - J Usha Raj
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL
- Children's Hospital University of Illinois, University of Illinois Hospital and Health Sciences System, Chicago, IL
| | - Guofei Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL
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41
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Maron BA, Machado RF, Shimoda L. Pulmonary vascular and ventricular dysfunction in the susceptible patient (2015 Grover Conference series). Pulm Circ 2016; 6:426-438. [PMID: 28090285 PMCID: PMC5210067 DOI: 10.1086/688315] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/21/2016] [Indexed: 12/14/2022] Open
Abstract
Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.
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Affiliation(s)
- Bradley A. Maron
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA; and Department of Cardiology, Boston Veterans Affairs Healthcare System, Boston, Massachusetts, USA
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Larissa Shimoda
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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42
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Barnes EA, Chen CH, Sedan O, Cornfield DN. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension. FASEB J 2016; 31:650-662. [PMID: 27811062 DOI: 10.1096/fj.201600557r] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 10/17/2016] [Indexed: 11/11/2022]
Abstract
Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive control patients and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.
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Affiliation(s)
- Elizabeth A Barnes
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, USA
| | - Chih-Hsin Chen
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, USA
| | - Oshra Sedan
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, USA
| | - David N Cornfield
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, USA
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43
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Lei W, He Y, Shui X, Li G, Yan G, Zhang Y, Huang S, Chen C, Ding Y. Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension. Mol Med Rep 2016; 14:4383-4390. [PMID: 27667582 DOI: 10.3892/mmr.2016.5752] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 07/22/2016] [Indexed: 11/06/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and structural remodeling of the pulmonary vasculature, mediated initially by reduced oxygen availability in the lungs. Hypoxia inducible factor (HIF), consisting of the functional subunit, HIF‑1α, and the constitutively expressed HIF‑1β, is involved in the pathological processes associated with hypoxia. In the current study, the sequences of cDNAs and amino acids of HIF were characterized and analyzed using online bioinformatics tools. To further evaluate whether HIF accounts for the occurrence of PAH, the present study determine the expression and phosphorylation levels of HIF and its associated pathways, including extracellular signal‑regulated kinase (Erk)1/2 and phosphoinositide 3‑kinase (PI3K)/Akt, in the lungs of patients with PAH by reverse transcription‑quantitative polymerase chain reaction and western blotting. The mRNA expression levels of PI3K, Erk2, and HIF‑1α in the patients with PAH were significantly higher, compared with those in the control group, by 3.6‑fold (P<0.01), 4.06‑fold and 2.64‑fold (P<0.05), respectively. No significant differences were found in the mRNA and protein levels of Akt between the two groups (P>0.05). The protein levels of phosphorylated (p‑)Akt, Erk1/2, p‑Erk1/2, HIF‑1α and HIF‑1β were significantly increased by 5.89‑, 0.5‑, 0.59‑, 1.46‑ and 0.92‑fold, respectively, in the patients with PAH, compared with those in the controls group (P<0.01 for p‑Akt, Erk1/2; P<0.05 for p‑Erk1/2, HIF‑1α and HIF‑1β). These findings suggested that the mitogen‑activated protein kinase and PI3K/Akt signaling pathways, and HIF‑1 may perform a specific function in the pathogenesis of PAH.
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Affiliation(s)
- Wei Lei
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Yuan He
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Xiaorong Shui
- Laboratory of Vascular Surgery, Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Guoming Li
- Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Guosen Yan
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Yu Zhang
- Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Shian Huang
- Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Can Chen
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Yuanlin Ding
- Institute of Medical Systems Biology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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44
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Mokas S, Larivière R, Lamalice L, Gobeil S, Cornfield DN, Agharazii M, Richard DE. Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification. Kidney Int 2016; 90:598-609. [PMID: 27470678 DOI: 10.1016/j.kint.2016.05.020] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 05/12/2016] [Accepted: 05/19/2016] [Indexed: 12/21/2022]
Abstract
Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG-4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1α subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions.
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Affiliation(s)
- Sophie Mokas
- Department of Molecular Biology, Medical Biochemistry, and Pathology, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada
| | - Richard Larivière
- Department of Medicine, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada
| | - Laurent Lamalice
- Department of Molecular Biology, Medical Biochemistry, and Pathology, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada
| | - Stéphane Gobeil
- Department of Molecular Medicine, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada
| | - David N Cornfield
- Center for Excellence in Pulmonary Biology, Stanford University, Stanford, California, USA
| | - Mohsen Agharazii
- Department of Medicine, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada
| | - Darren E Richard
- Department of Molecular Biology, Medical Biochemistry, and Pathology, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada.
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45
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The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice. Mol Cell Biol 2016; 36:1584-94. [PMID: 26976644 DOI: 10.1128/mcb.01055-15] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 03/09/2016] [Indexed: 11/20/2022] Open
Abstract
Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.
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Non-muscle myosin light chain promotes endothelial progenitor cells senescence and dysfunction in pulmonary hypertensive rats through up-regulation of NADPH oxidase. Eur J Pharmacol 2016; 775:67-77. [PMID: 26872992 DOI: 10.1016/j.ejphar.2016.02.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Revised: 01/26/2016] [Accepted: 02/08/2016] [Indexed: 02/06/2023]
Abstract
Non-muscle myosin regulatory light chain (nmMLC20) is reported to exert transcriptional function in regulation of gene expression, and NADPH oxidase (NOX)-derived reactive oxygen species contribute to vascular remodeling of pulmonary artery hypertension (PAH). This study aims to determine if nmMLC20 can promote endothelial progenitor cells (EPCs) senescence and dysfunction through up-regulation of NOX in PAH rats. The rats were exposed to10% hypoxia for 3 weeks to establish a PAH model, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, and the accelerated senescence and impaired functions in EPCs, accompanied by an increase in Rho-kinase (ROCK) and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil, a selective inhibitor of ROCK. Next, normal EPCs were cultured under hypoxia to induce senescence in vitro. Consistent with the in vivo findings, hypoxia increased the senescence and dysfunction of EPCs concomitant with an increase in ROCK and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil. Knockdown of nmMLC20 showed similar results to that of fasudil except no effect on ROCK activity. Based on these observations, we conclude that nmMLC20 could promote the senescence and dysfunctions of EPCs in PAH through up-regulation of NOX in a phosphorylation-dependent manner.
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47
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Siemsen DW, Dobrinen E, Han S, Chiocchi K, Meissner N, Swain SD. Vascular Dysfunction in Pneumocystis-Associated Pulmonary Hypertension Is Related to Endothelin Response and Adrenomedullin Concentration. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 186:259-69. [PMID: 26687815 DOI: 10.1016/j.ajpath.2015.10.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/29/2015] [Accepted: 10/22/2015] [Indexed: 10/22/2022]
Abstract
Pulmonary hypertension subsequent to an infectious disease can be due to vascular structural remodeling or to functional alterations within various vascular cell types. In our previous mouse model of Pneumocystis-associated pulmonary hypertension, we found that vascular remodeling was not responsible for observed increases in right ventricular pressures. Here, we report that the vascular dysfunction we observed could be explained by an enhanced response to endothelin-1 (20% greater reduction in lumen diameter, P ≤ 0.05), corresponding to an up-regulation of similar magnitude (P ≤ 0.05) of the endothelin A receptor in the lung tissue. This effect was potentially augmented by a decrease in production of the pulmonary vasodilator adrenomedullin of almost 70% (P ≤ 0.05). These changes did not occur in interferon-γ knockout mice similarly treated, which do not develop pulmonary hypertension under these circumstances. Surprisingly, we did not observe any relevant changes in the vascular endothelial nitric oxide synthase vasodilatory response, which is a common potential site of inflammatory alterations to pulmonary vascular function. Our results indicate the diverse mechanisms by which inflammatory responses to prior infections can cause functionally relevant changes in vascular responses in the lung, promoting the development of pulmonary hypertension.
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Affiliation(s)
- Dan W Siemsen
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Erin Dobrinen
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Soo Han
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Kari Chiocchi
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Nicole Meissner
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Steve D Swain
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana.
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48
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Veith C, Schermuly RT, Brandes RP, Weissmann N. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension. J Physiol 2015; 594:1167-77. [PMID: 26228924 DOI: 10.1113/jp270689] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/28/2015] [Indexed: 12/18/2022] Open
Abstract
Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes.
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Affiliation(s)
- Christine Veith
- Universities of Giessen and Marburg Lung Centre (UGMLC), member of the German Centre for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392, Giessen, Germany
| | - Ralph T Schermuly
- Universities of Giessen and Marburg Lung Centre (UGMLC), member of the German Centre for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392, Giessen, Germany
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University Frankfurt, ECCPS, 60590, Frankfurt, Germany
| | - Norbert Weissmann
- Universities of Giessen and Marburg Lung Centre (UGMLC), member of the German Centre for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392, Giessen, Germany
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49
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Abstract
Hypoxia inducible factors (HIFs) are α/β heterodimeric transcription factors that direct multiple cellular and systemic responses in response to changes in oxygen availability. The oxygen sensitive signal is generated by a series of iron and 2-oxoglutarate-dependent dioxygenases that catalyze post-translational hydroxylation of specific prolyl and asparaginyl residues in HIFα subunits and thereby promote their destruction and inactivation in the presence of oxygen. In hypoxia, these processes are suppressed allowing HIF to activate a massive transcriptional cascade. Elucidation of these pathways has opened several new fields of cardiovascular research. Here, we review the role of HIF hydroxylase pathways in cardiac development and in cardiovascular control. We also consider the current status, opportunities, and challenges of therapeutic modulation of HIF hydroxylases in the therapy of cardiovascular disease.
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Affiliation(s)
- Tammie Bishop
- From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Peter J Ratcliffe
- From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
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50
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Adeoye OO, Silpanisong J, Williams JM, Pearce WJ. Role of the sympathetic autonomic nervous system in hypoxic remodeling of the fetal cerebral vasculature. J Cardiovasc Pharmacol 2015; 65:308-16. [PMID: 25853949 PMCID: PMC4391294 DOI: 10.1097/fjc.0000000000000192] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Fetal hypoxia triggers compensatory angiogenesis and remodeling through mechanisms not fully elucidated. In response to hypoxia, hypoxia-inducible factor drives expression of cytokines that exert multiple effects on cerebral structures. Among these, the artery wall is composed of a heterogeneous cell mix and exhibits distinct patterns of cellular differentiation and reactivity. Governing these patterns are the vascular endothelium, smooth muscle (SM), adventitia, sympathetic perivascular nerves (SPN), and the parenchyma. Although an extensive literature details effects of nonneuronal factors on cerebral arteries, the trophic role of perivascular nerves remains unclear. Hypoxia increases sympathetic innervation with subsequent release of norepinephrine (NE), neuropeptide-Y (NPY), and adenosine triphosphate, which exert motor and trophic effects on cerebral arteries and influence dynamic transitions among SM phenotypes. Our data also suggest that the cerebrovasculature reacts very differently to hypoxia in fetuses and adults, and we hypothesize that these differences arise from age-related differences in arterial SM phenotype reactivity and proximity to trophic factors, particularly of neural origin. We provide an integration of recent literature focused on mechanisms by which SPN mediate hypoxic remodeling. Our recent findings suggest that trophic effects of SPN on cerebral arteries accelerate functional maturation through shifts in SM phenotype in an age-dependent manner.
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MESH Headings
- Adenosine Triphosphate/metabolism
- Adult
- Age Factors
- Animals
- Cerebrovascular Circulation
- Fetal Hypoxia/complications
- Fetal Hypoxia/metabolism
- Fetal Hypoxia/physiopathology
- Humans
- Hypoxia, Brain/complications
- Hypoxia, Brain/metabolism
- Hypoxia, Brain/physiopathology
- Muscle, Smooth, Vascular/innervation
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Neovascularization, Pathologic/etiology
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/physiopathology
- Neuropeptide Y/metabolism
- Norepinephrine/metabolism
- Sympathetic Nervous System/metabolism
- Sympathetic Nervous System/physiopathology
- Vascular Remodeling
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Affiliation(s)
- Olayemi O Adeoye
- Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA
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