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Selvadurai Y, Le Fevre ER, Mervis J, Fitzgerald DA. Hereditary haemorrhagic telangiectasia: A primer for the paediatrician. Paediatr Respir Rev 2025; 53:30-34. [PMID: 39214822 DOI: 10.1016/j.prrv.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by small telangiectasias and larger multisystem arteriovenous malformations (AVMs). Common sites of AVMs include in the nose, lungs, brain and liver. These lesions are prone to rupture, leading to complications including recurrent epistaxis and significant haemorrhage. Pulmonary hypertension (PH) can also occur. This review presents an update on the genetics, clinical manifestations, management options, and screening recommendations for children with HHT.
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Affiliation(s)
- Yoshua Selvadurai
- Department of Surgery, Gosford Hospital, Central Coast Local Health District, Holden Street, Gosford, NSW 2250, Australia
| | - Emily R Le Fevre
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
| | - Jonathan Mervis
- Heart Centre for Children, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia
| | - Dominic A Fitzgerald
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales 2145, Australia
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2
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Geng S, Hu B, Guan Y, Jiang Y, Shu Z, Li C, Huang G. Advances of the multifaceted functions of PSTPIP2 in inflammatory diseases. Front Immunol 2024; 15:1492878. [PMID: 39660128 PMCID: PMC11628490 DOI: 10.3389/fimmu.2024.1492878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 11/07/2024] [Indexed: 12/12/2024] Open
Abstract
The complex interaction between the immune system and autoinflammatory disorders highlights the centrality of autoimmune mechanisms in the pathogenesis of autoinflammatory diseases. With the exploration of PSTPIP2, it has been discovered to play an inhibitory role in immune diseases, suggesting its potential utility in the research and treatment of rheumatic diseases. This review outlines the mechanisms of PSTPIP2 in chronic multifocal osteomyelitis (CMO), rheumatoid arthritis (RA), synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, liver diseases, renal diseases, pressure ulcer sepsis and diabetic obesity. The mechanisms include inhibiting the IL-1β inflammatory responses, NF-κB, ERK phosphorylation etc., promoting Erβ, and modulating the polarization of macrophage to prevent the inflammatory diseases. This review summarized current findings and offered perspectives on future research directions, laying a foundation for applying of PSTPIP2 in inflammatory diseases.
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Affiliation(s)
- Shaohui Geng
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Bohan Hu
- School of Chinese Materia Medica , Beijing University of Chinese Medicine, Beijing, China
| | - Yiwei Guan
- School of Chinese Materia Medica , Beijing University of Chinese Medicine, Beijing, China
| | - Yijin Jiang
- School of Chinese Materia Medica , Beijing University of Chinese Medicine, Beijing, China
| | - Zixuan Shu
- School of Chinese Materia Medica , Beijing University of Chinese Medicine, Beijing, China
| | - Chen Li
- Department of Rheumatology, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guangrui Huang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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3
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Al-Samkari H. How I treat bleeding in hereditary hemorrhagic telangiectasia. Blood 2024; 144:940-954. [PMID: 38864625 PMCID: PMC11830975 DOI: 10.1182/blood.2023021765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/07/2024] [Accepted: 06/08/2024] [Indexed: 06/13/2024] Open
Abstract
ABSTRACT Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) affects 1 in 5000 persons, making it the second most common inherited bleeding disorder worldwide. Telangiectatic bleeding, primarily causing recurrent epistaxis and chronic gastrointestinal bleeding, is the most common and most important manifestation of this multisystem vascular disorder. HHT-associated bleeding results in substantial psychosocial morbidity and iron deficiency anemia that may be severe. Although there remain no regulatory agency-approved therapies for HHT, multiple large studies, including randomized controlled trials, have demonstrated the safety and efficacy of antifibrinolytics for mild-to-moderate bleeding manifestations and systemic antiangiogenic drugs including pomalidomide and bevacizumab for moderate-to-severe bleeding. This has led to a recent paradigm shift away from repetitive temporizing procedural management toward effective systemic medical therapeutics to treat bleeding in HHT. In this article, 4 patient cases are used to illustrate the most common and most challenging presentations of HHT-associated bleeding that hematologists are likely to encounter in daily practice. Built on a framework of published data and supported by extensive clinical experience, guidance is given for modern evidence-based approaches to antifibrinolytic therapy, antiangiogenic therapy, and iron deficiency anemia management across the HHT disease severity spectrum.
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Affiliation(s)
- Hanny Al-Samkari
- Division of Hematology Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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4
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Litsou E, Basiari L, Tsirves G, Psychogios GV. Hereditary Hemorrhagic Telangiectasia With Multiple Ear, Nose, and Throat (ENT) Manifestations: A Case Report. Cureus 2023; 15:e42706. [PMID: 37654935 PMCID: PMC10467641 DOI: 10.7759/cureus.42706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2023] [Indexed: 09/02/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant multisystem disorder. It is a mucocutaneous and fibrovascular dysplasia, the diagnosis of which is based on the fulfillment of the four Curaçao criteria: 1) recurrent epistaxis; 2) dermatovascular mucosal telangiectasias at characteristic sites: skin of the face, ears, fingertips, lips, tongue, and oral and nasal cavity; 3) arteriovenous malformations (AVMs) of visceral organs and central nervous system; and 4) family history: diagnosis of HHT in a first-degree relative. We describe a case of a 76-year-old patient who presented to our department with clinical manifestations of HHT in the skin (face, fingertips), lips, hard palate, tongue, ears, and nasal cavities. Individual and family history was obtained, as well as clinical laboratory examination, pan-endoscopy of the ear, nose, and throat (ENT) systems, and treatment of active foci of bleeding from the above areas. The otolaryngologist may be the first doctor to suspect Rendu-Osler-Weber syndrome and the one responsible for treating patients with HHT since recurrent epistaxis is the most frequent (90-96% of patients) and the earlier manifestation of the disease and the main reason for the arrival of these patients in the Emergency Department. The purpose of this study is to present a clinical case of Rendu-Osler-Weber syndrome with multiple ENT manifestations, as well as a review of the literature on their management and treatment.
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Affiliation(s)
- Eleni Litsou
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Ioannina, Ioannina, GRC
| | - Lentiona Basiari
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Ioannina, Ioannina, GRC
| | - Georgios Tsirves
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Ioannina, Ioannina, GRC
| | - Georgios V Psychogios
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Ioannina, Ioannina, GRC
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5
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Devendran A, Kar S, Bailey R, Trivieri MG. The Role of Bone Morphogenetic Protein Receptor Type 2 ( BMPR2) and the Prospects of Utilizing Induced Pluripotent Stem Cells (iPSCs) in Pulmonary Arterial Hypertension Disease Modeling. Cells 2022; 11:3823. [PMID: 36497082 PMCID: PMC9741276 DOI: 10.3390/cells11233823] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR), causing right ventricular hypertrophy and ultimately death from right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are linked to approximately 80% of hereditary, and 20% of idiopathic PAH cases, respectively. While patients carrying a BMPR2 gene mutation are more prone to develop PAH than non-carriers, only 20% will develop the disease, whereas the majority will remain asymptomatic. PAH is characterized by extreme vascular remodeling that causes pulmonary arterial endothelial cell (PAEC) dysfunction, impaired apoptosis, and uncontrolled proliferation of the pulmonary arterial smooth muscle cells (PASMCs). To date, progress in understanding the pathophysiology of PAH has been hampered by limited access to human tissue samples and inadequacy of animal models to accurately mimic the pathogenesis of human disease. Along with the advent of induced pluripotent stem cell (iPSC) technology, there has been an increasing interest in using this tool to develop patient-specific cellular models that precisely replicate the pathogenesis of PAH. In this review, we summarize the currently available approaches in iPSC-based PAH disease modeling and explore how this technology could be harnessed for drug discovery and to widen our understanding of the pathophysiology of PAH.
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Affiliation(s)
- Anichavezhi Devendran
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sumanta Kar
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rasheed Bailey
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Maria Giovanna Trivieri
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Medicine, Cardiology Unit, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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6
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Wei T, Richter GT, Zhang H, Sun RW, Smith CH, Strub GM. Extracranial arteriovenous malformations demonstrate dysregulated TGF-β/BMP signaling and increased circulating TGF-β1. Sci Rep 2022; 12:16612. [PMID: 36198763 PMCID: PMC9534897 DOI: 10.1038/s41598-022-21217-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/23/2022] [Indexed: 12/03/2022] Open
Abstract
Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-β/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-β/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-β1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-β1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-β1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-β1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-β1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-β/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-β/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-β1 levels may be a useful indicator of treatment success.
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Affiliation(s)
- Ting Wei
- Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR, 72202, USA
| | - Gresham T Richter
- Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR, 72202, USA.,Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, 72205, USA
| | - Haihong Zhang
- Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR, 72202, USA.,Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, 72205, USA
| | - Ravi W Sun
- Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR, 72202, USA.,Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, 72205, USA
| | - Conor H Smith
- Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, 72205, USA
| | - Graham M Strub
- Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR, 72202, USA. .,Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, 72205, USA.
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7
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Hessels J, Kroon S, Boerman S, Nelissen RC, Grutters JC, Snijder RJ, Lebrin F, Post MC, Mummery CL, Mager JJ. Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study. J Clin Med 2022; 11:5280. [PMID: 36142926 PMCID: PMC9503120 DOI: 10.3390/jcm11185280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/31/2022] [Accepted: 08/31/2022] [Indexed: 11/29/2022] Open
Abstract
Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.
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Affiliation(s)
- Josefien Hessels
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Steven Kroon
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Sanne Boerman
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Rik C. Nelissen
- Department of Otorhinolaryngology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Jan C. Grutters
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
- Department of Pulmonology, University Medical Center Utrecht, Heidelberglaan 100, 3484 CX Utrecht, The Netherlands
| | - Repke J. Snijder
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Franck Lebrin
- Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Marco C. Post
- Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3484 CX Utrecht, The Netherlands or
- Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
| | - Christine L. Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Johannes-Jurgen Mager
- Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
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Pinkaew D, Martinez-Hackert E, Jia W, King MD, Miao F, Enger NR, Silakit R, Ramana K, Chen SY, Fujise K. Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation. Commun Biol 2022; 5:157. [PMID: 35197550 PMCID: PMC8866402 DOI: 10.1038/s42003-022-03112-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/28/2022] [Indexed: 11/21/2022] Open
Abstract
Fortilin is a 172-amino acid multifunctional protein present in both intra- and extracellular spaces. Although fortilin binds and regulates various cellular proteins, the biological role of extracellular fortilin remains unknown. Here we report that fortilin specifically interacts with TGF-β1 and prevents it from activating the TGF-β1 signaling pathway. In a standard immunoprecipitation-western blot assay, fortilin co-immunoprecipitates TGF-β1 and its isoforms. The modified ELISA assay shows that TGF-β1 remains complexed with fortilin in human serum. Both bio-layer interferometry and surface plasmon resonance (SPR) reveal that fortilin directly bind TGF-β1. The SPR analysis also reveals that fortilin and the TGF-β receptor II (TGFβRII) compete for TGF-β1. Both luciferase and secreted alkaline phosphatase reporter assays show that fortilin prevents TGF-β1 from activating Smad3 binding to Smad-binding element. Fortilin inhibits the phosphorylation of Smad3 in both quantitative western blot assays and ELISA. Finally, fortilin inhibits TGFβ-1-induced differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells. A computer-assisted virtual docking reveals that fortilin occupies the pocket of TGF-β1 that is normally occupied by TGFβRII and that TGF-β1 can bind either fortilin or TGFβRII at any given time. These data support the role of extracellular fortilin as a negative regulator of the TGF-β1 signaling pathway. Fortilin prevents the activation of the TGF-β1 receptor by occupying the pocket of TGF-β1 and competing with TGF-βRII to bind with TGF-β1. This inhibits Smad3 phosphorylation and the differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells.
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Affiliation(s)
- Decha Pinkaew
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Erik Martinez-Hackert
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA
| | - Wei Jia
- Department of Surgery, University of Missouri, Columbia, MO, 65212, USA
| | - Matthew D King
- Department of Chemistry and Biochemistry, Boise State University, Boise, ID, 83725, USA
| | - Fei Miao
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA.,Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nicole R Enger
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Runglawan Silakit
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Kota Ramana
- Department of Biochemistry, Noorda College of Osteopathic Medicine, Provo, UT, 84606, USA
| | - Shi-You Chen
- Department of Surgery, University of Missouri, Columbia, MO, 65212, USA
| | - Ken Fujise
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA.
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9
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Pruijsen JM, Kroon S, Mager JJ, Bungener LB, van der Doef HPJ. Tacrolimus in Gastrointestinal Bleeding in a Young Boy With Hereditary Hemorrhagic Telangiectasia. JPGN REPORTS 2021; 2:e133. [PMID: 37206467 PMCID: PMC10191567 DOI: 10.1097/pg9.0000000000000133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 08/12/2021] [Indexed: 05/21/2023]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease in which gastrointestinal bleeding is a rare presenting symptom in children. Gastrointestinal bleeding in children is treated locally by endoscopy. When a focus of bleeding cannot be reached by endoscopy, management of these patients can be challenging. Previous reports showed a favorable outcome of treatment with tacrolimus in an adult HHT patient with liver vascular malformations and epistaxis and in a HHT patient with pulmonary hypertension. We report the first pediatric HHT patient who benefited from tacrolimus treatment. Our case demonstrated a remarkable decline in blood transfusions and better quality of life during the period of tacrolimus treatment.
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Affiliation(s)
- Jessica M. Pruijsen
- From the Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Steven Kroon
- Department of Pulmonology, St. Antonius Hospital Nieuwegein, The Netherlands
| | - Johannes J. Mager
- Department of Pulmonology, St. Antonius Hospital Nieuwegein, The Netherlands
| | - Laura B. Bungener
- Department of Laboratory Medicine, Transplantation Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hubert P. J. van der Doef
- From the Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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10
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Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood 2021; 137:888-895. [PMID: 33171488 DOI: 10.1182/blood.2020008739] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) management is evolving because of the emergence and development of antiangiogenic therapies to eliminate bleeding telangiectasias and achieve hemostasis. This progress is reflected in recent clinical recommendations published in the Second International Guidelines for the Diagnosis and Treatment of HHT, in which systemic therapies including antiangiogenics and antifibrinolytics are now recommended as standard treatment options for bleeding. This review highlights the new recommendations especially relevant to hematologists in managing bleeding, anticoagulation, and anemia in patients with HHT.
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11
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Gomes SV, Rodrigues V, Nunes-Dos-Santos DL, Pereira ALA, Peres MA. The relationship between periodontal status and hyperglycemia after kidney transplantation. Clin Oral Investig 2021; 26:397-406. [PMID: 34196853 DOI: 10.1007/s00784-021-04011-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 05/24/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Several factors have been associated with hyperglycemia after kidney transplantation (KTx), including systemic inflammation. This study aimed to investigate the relationship between periodontal status and hyperglycemia in KTx patients. MATERIALS AND METHODS Forty-four KTx patients were included in this cross-sectional study. Periodontitis severity was categorized into stage I to IV. Fasting blood glucose (FBG) was measured, and hyperglycemia was analyzed at different FBG cutoff points (100 mg/dL, 110 mg/dL, 120 mg/dL, 126 mg/dL, 140 mg/dL). Age, history of smoking, prior type 2 diabetes (T2D), and prior cardiovascular disease (CVD) were considered cofounders. Multivariable logistic regression modelling was performed with periodontitis as the exposure and hyperglycemia as the outcome. Pathway analysis was performed with FBG as a continuous outcome. RESULTS Periodontitis had increased odds of hyperglycemia from 120 mg/dL FBG cutoff, even after adjustment. In addition, periodontitis severity was positively associated with FBG level (β = 0.323, SE = 0.127, P = 0.011). CONCLUSION The findings suggest that periodontitis may be related to increase of hyperglycemia and FBG levels in KTx patients. CLINICAL RELEVANCE Periodontitis severity and cardiovascular disease were positively associated with FBG levels in KTx patients. Clinicians and patients should be aware of the potential benefit of periodontal care for better glycemic control management.
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Affiliation(s)
- Samira V Gomes
- Dentistry Graduate Program, Federal University of Maranhão, Avenida Dos Portugueses, São Luís, 196665080-805, Brazil
| | - Vandilson Rodrigues
- Dentistry Graduate Program, Federal University of Maranhão, Avenida Dos Portugueses, São Luís, 196665080-805, Brazil. .,School of Dentistry and Oral Health, Griffith University, Gold Coast, QLD, Australia.
| | - Danila L Nunes-Dos-Santos
- Dentistry Graduate Program, Federal University of Maranhão, Avenida Dos Portugueses, São Luís, 196665080-805, Brazil
| | - Antonio L A Pereira
- Dentistry Graduate Program, Federal University of Maranhão, Avenida Dos Portugueses, São Luís, 196665080-805, Brazil
| | - Marco A Peres
- School of Dentistry and Oral Health, Griffith University, Gold Coast, QLD, Australia.,National Dental Research Institute Singapore, National Dental Centre Singapore, Singapore, Singapore.,Oral Health ACP, Health Services and Systems Research Programme, Duke-NUS Medical School, Singapore, Singapore
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12
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Bofarid S, Hosman AE, Mager JJ, Snijder RJ, Post MC. Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology. Int J Mol Sci 2021; 22:3471. [PMID: 33801690 PMCID: PMC8038106 DOI: 10.3390/ijms22073471] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/15/2022] Open
Abstract
In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.
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Affiliation(s)
- Sala Bofarid
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands;
| | - Anna E. Hosman
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Johannes J. Mager
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Repke J. Snijder
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Marco C. Post
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands;
- Department of Cardiology, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands
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13
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Snodgrass RO, Chico TJA, Arthur HM. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes (Basel) 2021; 12:174. [PMID: 33513792 PMCID: PMC7911152 DOI: 10.3390/genes12020174] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.
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Affiliation(s)
- Ryan O. Snodgrass
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Timothy J. A. Chico
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Helen M. Arthur
- Biosciences Institute, Centre for Life, Newcastle University, Newcastle NE1 3BZ, UK
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14
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Dunmore BJ, Jones RJ, Toshner MR, Upton PD, Morrell NW. Approaches to treat pulmonary arterial hypertension by targeting bmpr2 - from cell membrane to nucleus. Cardiovasc Res 2021; 117:2309-2325. [PMID: 33399862 DOI: 10.1093/cvr/cvaa350] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/06/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is estimated to affect between 10-50 people per million worldwide. The lack of cure and devastating nature of the disease means that treatment is crucial to arrest rapid clinical worsening. Current therapies are limited by their focus on inhibiting residual vasoconstriction rather than targeting key regulators of the cellular pathology. Potential disease-modifying therapies may come from research directed towards causal pathways involved in the cellular and molecular mechanisms of disease. It is widely acknowledged, that targeting reduced expression of the critical bone morphogenetic protein type-2 receptor (BMPR2) and its associated signalling pathways is a compelling therapeutic avenue to explore. In this review we highlight the advances that have been made in understanding this pathway and the therapeutics that are being tested in clinical trials and the clinic to treat PAH.
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Affiliation(s)
- Benjamin J Dunmore
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Rowena J Jones
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Mark R Toshner
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Paul D Upton
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Nicholas W Morrell
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
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15
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Ruiz S, Zhao H, Chandakkar P, Papoin J, Choi H, Nomura-Kitabayashi A, Patel R, Gillen M, Diao L, Chatterjee PK, He M, Al-Abed Y, Wang P, Metz CN, Oh SP, Blanc L, Campagne F, Marambaud P. Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models. J Clin Invest 2020; 130:942-957. [PMID: 31689244 DOI: 10.1172/jci127425] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 10/31/2019] [Indexed: 12/17/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.
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Affiliation(s)
- Santiago Ruiz
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Haitian Zhao
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | | | - Julien Papoin
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | - Hyunwoo Choi
- Barrow Aneurysm and AVM Research Center, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
| | | | - Radhika Patel
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Matthew Gillen
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Li Diao
- Center for Immunology and Inflammation
| | | | - Mingzhu He
- Center for Molecular Innovation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Yousef Al-Abed
- Center for Molecular Innovation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Christine N Metz
- Institute of Molecular Medicine, and.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - S Paul Oh
- Barrow Aneurysm and AVM Research Center, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Lionel Blanc
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Fabien Campagne
- The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and.,Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA
| | - Philippe Marambaud
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
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16
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Hwan Kim Y, Vu PN, Choe SW, Jeon CJ, Arthur HM, Vary CPH, Lee YJ, Oh SP. Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia. Circ Res 2020; 127:1122-1137. [PMID: 32762495 DOI: 10.1161/circresaha.119.316267] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
RATIONALE Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG, ALK1, or SMAD4. Since proteins from all 3 HHT genes are components of signal transduction of TGF-β (transforming growth factor β) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. OBJECTIVE We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. METHODS AND RESULTS We generated a novel mouse allele (ROSA26Alk1) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1- and Eng-inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng-iKO as well as Alk1-iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1-iKO models. CONCLUSIONS These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.
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Affiliation(s)
- Yong Hwan Kim
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ (Y.H.K., S.P.O.)
| | - Phuong-Nhung Vu
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)
| | - Se-Woon Choe
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of Korea (S.-w.C.)
| | - Chang-Jin Jeon
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Korea (C.J.J.)
| | - Helen M Arthur
- Institute of Genetic Medicine, Newcastle University, United Kingdom (H.M.A.)
| | - Calvin P H Vary
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (C.P.V.)
| | - Young Jae Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)
| | - S Paul Oh
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ (Y.H.K., S.P.O.)
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17
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Albiñana V, Cuesta AM, de Rojas-P I, Gallardo-Vara E, Recio-Poveda L, Bernabéu C, Botella LM. Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding. J Clin Med 2020; 9:E1766. [PMID: 32517280 PMCID: PMC7356836 DOI: 10.3390/jcm9061766] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/28/2020] [Accepted: 06/03/2020] [Indexed: 12/18/2022] Open
Abstract
The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at "ground zero" to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.
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Affiliation(s)
- Virginia Albiñana
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III, 28040 Madrid, Spain
| | - Angel M. Cuesta
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III, 28040 Madrid, Spain
| | - Isabel de Rojas-P
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
| | - Eunate Gallardo-Vara
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA;
| | - Lucía Recio-Poveda
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III, 28040 Madrid, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III, 28040 Madrid, Spain
| | - Luisa María Botella
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 9 Ramiro de Maeztu Street, 28040 Madrid, Spain; (V.A.); (A.M.C.); (I.d.R.-P.); (L.R.-P.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III, 28040 Madrid, Spain
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18
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Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial. J Clin Med 2020; 9:jcm9051262. [PMID: 32357559 PMCID: PMC7287684 DOI: 10.3390/jcm9051262] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 01/10/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.
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19
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Garelja M, Au M, Brimble MA, Gingell JJ, Hendrikse ER, Lovell A, Prodan N, Sexton PM, Siow A, Walker CS, Watkins HA, Williams GM, Wootten D, Yang SH, Harris PWR, Hay DL. Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors. ACS Pharmacol Transl Sci 2020; 3:246-262. [PMID: 32296766 PMCID: PMC7155197 DOI: 10.1021/acsptsci.9b00083] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Indexed: 02/07/2023]
Abstract
Adrenomedullin (AM) is a 52 amino acid peptide that plays a regulatory role in the vasculature. Receptors for AM comprise the class B G protein-coupled receptor, the calcitonin-like receptor (CLR), in complex with one of three receptor activity-modifying proteins (RAMPs). The C-terminus of AM is involved in binding to the extracellular domain of the receptor, while the N-terminus is proposed to interact with the juxtamembranous portion of the receptor to activate signaling. There is currently limited information on the molecular determinants involved in AM signaling, thus we set out to define the importance of the AM N-terminus through five signaling pathways (cAMP production, ERK phosphorylation, CREB phosphorylation, Akt phosphorylation, and IP1 production). We characterized the three CLR:RAMP complexes through the five pathways, finding that each had a distinct repertoire of intracellular signaling pathways that it is able to regulate. We then performed an alanine scan of AM from residues 15-31 and found that most residues could be substituted with only small effects on signaling, and that most substitutions affected signaling through all receptors and pathways in a similar manner. We identify F18, T20, L26, and I30 as being critical for AM function, while also identifying an analogue (AM15-52 G19A) which has unique signaling properties relative to the unmodified AM. We interpret our findings in the context of new structural information, highlighting the complementary nature of structural biology and functional assays.
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Affiliation(s)
- Michael
L. Garelja
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Maggie Au
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
| | - Margaret A. Brimble
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
- School
of Chemical Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Joseph J. Gingell
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
| | - Erica R. Hendrikse
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Annie Lovell
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Nicole Prodan
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Patrick M. Sexton
- Drug
Discovery Biology and Department of Pharmacology, Monash Institute
of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Andrew Siow
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- School
of Chemical Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Christopher S. Walker
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
| | - Harriet A. Watkins
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
| | - Geoffrey M. Williams
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
- School
of Chemical Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Denise Wootten
- Drug
Discovery Biology and Department of Pharmacology, Monash Institute
of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Sung H. Yang
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
| | - Paul W. R. Harris
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
- School
of Chemical Sciences, University of Auckland, Auckland, 1010, New Zealand
| | - Debbie L. Hay
- School
of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand
- Maurice
Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand
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20
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Robert F, Desroches-Castan A, Bailly S, Dupuis-Girod S, Feige JJ. Future treatments for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2020; 15:4. [PMID: 31910860 PMCID: PMC6945546 DOI: 10.1186/s13023-019-1281-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022] Open
Abstract
Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.
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Affiliation(s)
- Florian Robert
- Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000, Grenoble, France
| | - Agnès Desroches-Castan
- Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000, Grenoble, France
| | - Sabine Bailly
- Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000, Grenoble, France
| | - Sophie Dupuis-Girod
- Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000, Grenoble, France.,Hospices Civils de Lyon, Service de Génétique, Hôpital Femme-Mère-Enfants, F-69677, Bron, France.,Centre National de Référence pour la Maladie de Rendu-Osler, F-69677, Bron, France
| | - Jean-Jacques Feige
- Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000, Grenoble, France.
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21
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Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings. J Clin Med 2019; 9:jcm9010082. [PMID: 31905627 PMCID: PMC7019907 DOI: 10.3390/jcm9010082] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/20/2019] [Accepted: 12/25/2019] [Indexed: 12/11/2022] Open
Abstract
Background: We aimed to describe risk factors for gastrointestinal (GI) bleeding and endoscopic findings in patients with hereditary hemorrhagic telangiectasia (HHT). Methods: This is a prospective study from a referral HHT unit. Endoscopic tests were performed when there was suspicion of GI bleeding, and patients were divided as follows: with, without, and with unsuspected GI involvement. Results: 67 (27.9%) patients with, 28 (11.7%) patients without, and 145 (60.4%) with unsuspected GI involvement were included. Age, tobacco use, endoglin (ENG) mutation, and hemoglobin were associated with GI involvement. Telangiectases were mostly in the stomach and duodenum, but 18.5% of patients with normal esophagogastroduodenoscopy (EGD) had GI involvement in video capsule endoscopy (VCE). Telangiectases ≤ 3 mm and ≤10 per location were most common. Among patients with GI disease, those with hemoglobin < 8 g/dL or transfusion requirements (65.7%) were older and had higher epistaxis severity score (ESS) and larger telangiectases (>3 mm). After a mean follow-up of 34.2 months, patients with GI involvement required more transfusions and more emergency department and hospital admissions, with no differences in mortality. Conclusions: Risk factors for GI involvement have been identified. Patients with GI involvement and severe anemia had larger telangiectases and higher ESS. VCE should be considered in patients with suspicion of GI bleeding, even if EGD is normal.
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22
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Albiñana V, Giménez-Gallego G, García-Mato A, Palacios P, Recio-Poveda L, Cuesta AM, Patier JL, Botella LM. Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition). TH OPEN 2019; 3:e230-e243. [PMID: 31360828 PMCID: PMC6660472 DOI: 10.1055/s-0039-1693710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/13/2019] [Indexed: 12/16/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in
Endoglin
and
ACVRL1
/
ALK1
, genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016–003982–24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).
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Affiliation(s)
- Virginia Albiñana
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Angela García-Mato
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
| | - Patricia Palacios
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
| | - Lucia Recio-Poveda
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
| | - Angel-M Cuesta
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - José-Luis Patier
- Department of Internal Medicine, University Hospital Ramón y Cajal; Department of Medicine and Medical Specialities, Faculty of Medicine, University of Alcalá, IRYCIS, Madrid, Spain
| | - Luisa-María Botella
- Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
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Abstract
Osler's disease is an autosomal dominant hereditary syndrome which belongs to the group of orphan diseases. Affected patients suffer primarily from severe epistaxis. Diagnosis is based on the Curaçao criteria and molecular genetic tests. Organ manifestations can be found in the form of arteriovenous shunts in the lung, liver, and gastrointestinal tract; more rarely also in the central nervous system (CNS) and other parts of the body. Many patients with gastrointestinal and other organ manifestations are frequently clinically asymptomatic; therefore, organ screening is essential to avoid later complications and should be performed in centers with particular expertise. No curative therapy currently exists. From the otolaryngologist's perspective, nasal mucosa treatments and endonasal laser applications are important and effective therapeutic approaches to epistaxis. Pharmacological interventions are focused on compensation of haploinsufficiency as well as antiangiogenetic approaches. Severe side effects have to be considered.
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24
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Paolacci S, Zulian A, Bruson A, Manara E, Michelini S, Mattassi RE, Lee BB, Amato B, Bertelli M. Vascular anomalies: molecular bases, genetic testing and therapeutic approaches. INT ANGIOL 2019; 38:157-170. [DOI: 10.23736/s0392-9590.19.04154-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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25
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Peiffer BJ, Qi L, Ahmadi AR, Wang Y, Guo Z, Peng H, Sun Z, Liu JO. Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing. Cell Chem Biol 2019; 26:652-661.e4. [PMID: 30827938 DOI: 10.1016/j.chembiol.2019.01.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/04/2018] [Accepted: 01/24/2019] [Indexed: 01/05/2023]
Abstract
The combination of AMD3100 and low-dose FK506 has been shown to accelerate wound healing in vivo. Although AMD3100 is known to work by releasing hematopoietic stem cells into circulation, the mechanism of FK506 in this setting has remained unknown. In this study, we investigated the activities of FK506 in human cells and a diabetic-rat wound model using a non-immunosuppressive FK506 analog named FKVP. While FKVP was incapable of inhibiting calcineurin, wound-healing enhancement with AMD3100 was unaffected. Further study showed that both FK506 and FKVP activate BMP signaling in multiple cell types through FKBP12 antagonism. Furthermore, selective inhibition of BMP signaling abolished stem cell recruitment and wound-healing enhancement by combination treatment. These results shed new light on the mechanism of action of FK506 in acceleration of wound healing, and raise the possibility that less toxic FKBP ligands such as FKVP can replace FK506 for the treatment of chronic wounds.
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Affiliation(s)
- Brandon J Peiffer
- Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Le Qi
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Ali R Ahmadi
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Yuefan Wang
- Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Zufeng Guo
- Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Hanjing Peng
- Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
| | - Jun O Liu
- Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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26
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Galaris G, Thalgott JH, Lebrin FPG. Pericytes in Hereditary Hemorrhagic Telangiectasia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:215-246. [PMID: 31147880 DOI: 10.1007/978-3-030-16908-4_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.
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Affiliation(s)
- Georgios Galaris
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jérémy H Thalgott
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Franck P G Lebrin
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
- Physics for Medicine, ESPCI, INSERM U1273, CNRS, Paris, France.
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France.
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27
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Vorselaars VMM, Hosman AE, Westermann CJJ, Snijder RJ, Mager JJ, Goumans MJ, Post MC. Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia. Int J Mol Sci 2018; 19:ijms19103203. [PMID: 30336550 PMCID: PMC6213989 DOI: 10.3390/ijms19103203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 12/20/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.
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Affiliation(s)
| | - Anna E Hosman
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | | | - Repke J Snijder
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | - Johannes J Mager
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | - Marie-Jose Goumans
- Department of Molecular Cell Biology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands.
| | - Marco C Post
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
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28
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Roman BL, Hinck AP. ALK1 signaling in development and disease: new paradigms. Cell Mol Life Sci 2017; 74:4539-4560. [PMID: 28871312 PMCID: PMC5687069 DOI: 10.1007/s00018-017-2636-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 08/01/2017] [Accepted: 08/28/2017] [Indexed: 12/21/2022]
Abstract
Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.
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Affiliation(s)
- Beth L Roman
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, 130 DeSoto St, Pittsburgh, PA, 15261, USA.
| | - Andrew P Hinck
- Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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29
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Abstract
Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.
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Affiliation(s)
- Sara I Cunha
- From the Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden (S.I.C., P.U.M., E.D.); FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); and Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.)
| | - Peetra U Magnusson
- From the Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden (S.I.C., P.U.M., E.D.); FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); and Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.)
| | - Elisabetta Dejana
- From the Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden (S.I.C., P.U.M., E.D.); FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); and Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
| | - Maria Grazia Lampugnani
- From the Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden (S.I.C., P.U.M., E.D.); FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); and Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.)
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30
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Ruiz-Llorente L, Gallardo-Vara E, Rossi E, Smadja DM, Botella LM, Bernabeu C. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets 2017; 21:933-947. [PMID: 28796572 DOI: 10.1080/14728222.2017.1365839] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level. Areas covered: Pathogenic mutations in genes coding for the TGF-β receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed. Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.
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Affiliation(s)
- Lidia Ruiz-Llorente
- a Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , Madrid , Spain
| | - Eunate Gallardo-Vara
- a Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , Madrid , Spain
| | - Elisa Rossi
- b Faculté de Pharmacie , Paris Descartes University, Sorbonne Paris Cité and Inserm UMR-S1140 , Paris , France
| | - David M Smadja
- b Faculté de Pharmacie , Paris Descartes University, Sorbonne Paris Cité and Inserm UMR-S1140 , Paris , France
| | - Luisa M Botella
- a Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , Madrid , Spain
| | - Carmelo Bernabeu
- a Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , Madrid , Spain
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31
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Albiñana V, Recio-Poveda L, Zarrabeitia R, Botella LM. Current and emerging pharmacotherapies for hereditary hemorrhagic telangiectasia. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1353417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Virginia Albiñana
- Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
- Medical Genetics Groug, U-707 CIBERer (Network of Biomedicine Investigation Centers on Rare diseases)
| | | | - Roberto Zarrabeitia
- Medical Genetics Groug, U-707 CIBERer (Network of Biomedicine Investigation Centers on Rare diseases)
- Department of Internal Medicine, Hospital de Sierrallana, Cantabria, Spain
| | - Luisa M. Botella
- Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
- Medical Genetics Groug, U-707 CIBERer (Network of Biomedicine Investigation Centers on Rare diseases)
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32
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BMP type II receptor as a therapeutic target in pulmonary arterial hypertension. Cell Mol Life Sci 2017; 74:2979-2995. [PMID: 28447104 PMCID: PMC5501910 DOI: 10.1007/s00018-017-2510-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/09/2017] [Accepted: 03/17/2017] [Indexed: 12/30/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies.
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Robaina Cabrera DM, Verde González MP, Tarazona Chocano B, Amado Fernández C, Zarrabeitia Puente R. Telangiectasia hemorrágica hereditaria: enfermedad de Rendu-Osler-Weber. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/j.fmc.2016.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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34
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Zarrabeitia R, Ojeda-Fernandez L, Recio L, Bernabéu C, Parra JA, Albiñana V, Botella LM. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia. Thromb Haemost 2016; 115:1167-77. [PMID: 26818701 DOI: 10.1160/th15-03-0239] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 01/25/2016] [Indexed: 01/16/2023]
Abstract
Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).
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Affiliation(s)
| | | | | | | | | | | | - Luisa M Botella
- Luisa M. Botella, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, Madrid, 28040 Spain, E-mail:
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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Ardelean DS, Letarte M. Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia. Front Genet 2015; 6:35. [PMID: 25717337 PMCID: PMC4324154 DOI: 10.3389/fgene.2015.00035] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 01/26/2015] [Indexed: 01/22/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic–angiostatic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic–angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.
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Affiliation(s)
- Daniela S Ardelean
- Department of Pediatrics, The Hospital for Sick Children Toronto, ON, Canada
| | - Michelle Letarte
- Molecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children Toronto, ON, Canada ; Department of Immunology, University of Toronto Toronto, ON, Canada ; Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto Toronto, ON, Canada
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Roman BL, Finegold DN. Genetic and Molecular Basis for Hereditary Hemorrhagic Telangiectasia. CURRENT GENETIC MEDICINE REPORTS 2014. [DOI: 10.1007/s40142-014-0061-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Pál G, Lovas G, Dobolyi A. Induction of transforming growth factor beta receptors following focal ischemia in the rat brain. PLoS One 2014; 9:e106544. [PMID: 25192322 PMCID: PMC4156357 DOI: 10.1371/journal.pone.0106544] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 08/07/2014] [Indexed: 01/02/2023] Open
Abstract
Transforming growth factor-βs (TGF-βs) regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI) and II receptors (TGF-βRII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII). TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were induced in the infarct area, while TGF-βRI and RII also appeared in the penumbra. Most cells with elevated TGF-βRI mRNA levels were microglia. TGF-βRII co-localized with both microglial and endothelial markers while TGF-βRIII and Alk1 were present predominantly in endothels. All four TGF-β receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-βRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-βRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-β receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-β receptor expression is preceded by increased TGF-β expression. TGF-βRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-βRII, and RIII in endothels within the infarct where TGF-β1 may be their ligand. At later time points, TGF-βRIII may also appear in glial cells to potentially affect signal transduction via TGF-βRI and RII.
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Affiliation(s)
- Gabriella Pál
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
| | - Gábor Lovas
- Department of Neurology, Semmelweis University, Budapest, Hungary
- Department of Neurology, Jahn Ferenc Teaching Hospital, Budapest, Hungary
| | - Arpád Dobolyi
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
- Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest, Hungary
- * E-mail:
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A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2013; 1829:1309-19. [PMID: 24189493 DOI: 10.1016/j.bbagrm.2013.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 10/18/2013] [Accepted: 10/28/2013] [Indexed: 11/22/2022]
Abstract
EDD (E3 isolated by differential display) was initially isolated as a progestin-regulated gene in breast cancer cells, and represents the human ortholog of the Drosophila melanogaster hyperplastic discs gene (hyd). It encodes a highly conserved and predominantly nuclear ubiquitin E3 ligase of the HECT family, with potential multifunctional roles in development and tumorigenesis. In this study, we further examined the largely uncharacterized role of EDD in transcriptional regulation by uncovering the spectrum of its direct target genes at a genome-wide level. Use of a systematic approach that integrates gene expression and chromatin binding profiling identified several candidate EDD-target genes, one of which is ACVRL1, a TGF-β receptor with functional implications in blood vessel development. Further characterization revealed a negative regulation of ACVRL1 gene expression by EDD that is exerted at the promoter. Consistent with the aberrant upregulation of ACVRL1 and downstream Smad signaling, abrogation of EDD led to deregulated vessel development and endothelial cell motility. Collectively, these results extended the known cellular roles of EDD to critical functions in transcriptional regulation as well as angiogenesis, and may provide mechanistic explanations for EDD's tumorigenic and developmental roles.
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Galat A. Functional diversity and pharmacological profiles of the FKBPs and their complexes with small natural ligands. Cell Mol Life Sci 2013; 70:3243-75. [PMID: 23224428 PMCID: PMC11113493 DOI: 10.1007/s00018-012-1206-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Revised: 10/24/2012] [Accepted: 10/25/2012] [Indexed: 12/25/2022]
Abstract
From 5 to 12 FK506-binding proteins (FKBPs) are encoded in the genomes of disparate marine organisms, which appeared at the dawn of evolutionary events giving rise to primordial multicellular organisms with elaborated internal body plan. Fifteen FKBPs, several FKBP-like proteins and some splicing variants of them are expressed in humans. Human FKBP12 and some of its paralogues bind to different macrocyclic antibiotics such as FK506 or rapamycin and their derivatives. FKBP12/(macrocyclic antibiotic) complexes induce diverse pharmacological activities such as immunosuppression in humans, anticancerous actions and as sustainers of quiescence in certain organisms. Since the FKBPs bind to various assemblies of proteins and other intracellular components, their complexes with the immunosuppressive drugs may differentially perturb miscellaneous cellular functions. Sequence-structure relationships and pharmacological profiles of diverse FKBPs and their involvement in crucial intracellular signalization pathways and modulation of cryptic intercellular communication networks were discussed.
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Affiliation(s)
- Andrzej Galat
- Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, Institut de Biologie et de Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Bat. 152, 91191, Gif-sur-Yvette Cedex, France.
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Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, Rabinovitch M. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013; 123:3600-13. [PMID: 23867624 DOI: 10.1172/jci65592] [Citation(s) in RCA: 332] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 05/16/2013] [Indexed: 12/12/2022] Open
Abstract
Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.
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Affiliation(s)
- Edda Spiekerkoetter
- The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California 94305-5162, USA
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Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model. Brain Behav Immun 2013; 30:143-9. [PMID: 23257117 DOI: 10.1016/j.bbi.2012.12.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 11/26/2012] [Accepted: 12/09/2012] [Indexed: 02/03/2023] Open
Abstract
Cerebrovascular amyloidosis (CA) may result in intraparenchymal bleeding and cognitive impairment. It was previously shown that transforming growth factor-β1 (TGF-β1) expression under an astrocyte promoter resulted in congophilic vascular deposits and vascular pathology. A reduction in insulin-degrading enzyme (IDE) activity was previously suggested to play a role in the accumulation of congophilic vascular deposits in the microvasculature of Alzheimer's disease (AD) cases. Here, we aim to investigate the link between TGF-β1 and IDE activity in the development of CA. We found that TGF-β1 can reduce IDE expression in a mouse brain endothelial cell line (ECs). Furthermore, we discovered that IDE activity in the brains of TGF-β1 transgenic (Tg) mice was significantly reduced compared with that of the control mice in an age-dependent manner. In addition, TGF-β1/IDE(-/-) mice showed significantly greater levels of cerebrovascular pathology compared with TGF-β1 mice. We have previously shown that 16-month-old TGF-β1 mice have a significant reduction in synaptophysin protein levels, which may lead to cognitive impairment. Here we discovered a significant reduction in synaptophysin protein already at the age of seven in the hippocampus of TGF-β1/IDE(-/-) mice compared with TGF-β1 mice. Further investigation of TGF-β1-mediated IDE activity in ECs may provide useful therapeutic intervention targets for cerebrovascular diseases such as CA.
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ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells. Microvasc Res 2012; 85:46-53. [PMID: 23142694 DOI: 10.1016/j.mvr.2012.10.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 10/08/2012] [Indexed: 01/15/2023]
Abstract
BACKGROUND Many cases of pulmonary arterial hypertension (PAH) are heritable and related to gene mutations in bone morphogenic receptor-2 (BMPR2). These patients consequently may have a signaling imbalance within the transforming growth factor beta (TGFβ) receptor superfamily. The causes of increased endothelin-1 (ET-1), which contributes to PAH, are unknown, and we therefore studied the contribution of various BMPs and their receptors on ET-1 production in vitro, after knockdown of BMPR2 in human pulmonary microvascular endothelial cells (HMVEC-LBl). METHODOLOGY/PRINCIPAL FINDINGS Receptor knockdown in HMVEC-LBl was performed using siRNA to BMPR2, and activin like-kinases 1 and 2 (ALK1, ALK2). ET-1 and TGFβ levels in the medium were measured by ELISA. In some experiments, cells were exposed to TGFβ or BMP7 or FK506 (tacrolimus). Using Western blotting, levels of BMPR2, endothelin ET(B) receptor, phosphorylated SMAD 2 (pSMAD 2), phosphorylated SMAD 1,5 (pSMAD 1,5), ALK1, ALK2, ALK5, TGFβ receptor 2, plasminogen activator inhibitor-1 (PAI-1) and ID1 were measured. BMPR2 knockdown significantly increased ET-1 levels. It did not affect ET(B) receptor or TGFβ levels. TGFβ increased ET-1 levels, with or without BMPR2 knockdown. BMPR2 knockdown did not affect TGFβ (pSMAD 2 and PAI-1) signaling. BMP7 increased ET-1 levels after BMPR2 knockdown but this was prevented by ALK2 knockdown as was the increase in ID1 caused by BMPR2 knockdown. FK506, which interacts with ALK2, increased ET-1 levels and ID1 levels, and this was blocked by ALK2 knockdown. CONCLUSION/SIGNIFICANCE ALK2 may be an important receptor in ET-1 production during BMPR2 knockdown.
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Uebelhoer M, Boon LM, Vikkula M. Vascular anomalies: from genetics toward models for therapeutic trials. Cold Spring Harb Perspect Med 2012; 2:cshperspect.a009688. [PMID: 22908197 DOI: 10.1101/cshperspect.a009688] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Vascular anomalies are localized abnormalities that occur during vascular development. Several causative genes have been identified not only for inherited but also for some sporadic forms, and the molecular pathways involved are becoming understood. This gives us the opportunity to generate animals carrying the causative genetic defects, which we hope model the phenotype seen in human patients. These models would enable us not only to test known antiangiogenic drugs, but also to develop novel approaches for treatment, directly targeting the mutated protein or molecules implicated in the pathophysiological signaling pathways.
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Affiliation(s)
- Melanie Uebelhoer
- Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
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Albiñana V, Recio-Poveda L, Zarrabeitia R, Bernabéu C, Botella LM. Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. Thromb Haemost 2012; 108:41-53. [PMID: 22552254 DOI: 10.1160/th11-11-0809] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 04/01/2012] [Indexed: 12/13/2022]
Abstract
The β-blocker propranolol, originally designed for cardiological indications (angina, cardiac arrhythmias and high blood pressure), is nowadays, considered the most efficient drug for the treatment in infantile haemangiomas (IH), a vascular tumour that affects 5-10% of all infants. However, its potential therapeutic benefits in other vascular anomalies remain to be explored. In the present work we have assessed the impact of propranolol in endothelial cell cultures to test if this drug could be used in the vascular disease hereditary haemorrhagic telangiectasia (HHT). This rare disease is the result of abnormal angiogenesis with epistaxis, mucocutaneous and gastrointestinal telangiectases, as well as arteriovenous malformations in several organs, as clinical manifestations. Mutations in Endoglin (ENG) and ACVLR1 (ALK1) genes, lead to HHT1 and HHT2, respectively. Endoglin and ALK1 are involved in the TGF-β1 signalling pathway and play a critical role for the proper development of the blood vessels. As HHT is due to a deregulation of key angiogenic factors, inhibitors of angiogenesis have been used to normalise the nasal vasculature eliminating epistaxis derived from telangiectases. Thus, the antiangiogenic properties of propranolol were tested in endothelial cells. The drug was able to decrease cellular migration and tube formation, concomitantly with reduced RNA and protein levels of ENG and ALK1. Moreover, the drug showed apoptotic effects which could explain cell death in IH. Interestingly, propranolol showed some profibrinolytic activity, decreasing PAI-1 levels. These results suggest that local administration of propranolol in the nose mucosa to control epistaxis might be a potential therapeutic approach in HHT.
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Affiliation(s)
- Virginia Albiñana
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
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Zhang W, Zeng Z, Fan S, Wang J, Yang J, Zhou Y, Li X, Huang D, Liang F, Wu M, Tang K, Cao L, Li X, Xiong W, Li G. Evaluation of the prognostic value of TGF-β superfamily type I receptor and TGF-β type II receptor expression in nasopharyngeal carcinoma using high-throughput tissue microarrays. J Mol Histol 2012; 43:297-306. [PMID: 22391627 DOI: 10.1007/s10735-012-9392-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Accepted: 02/07/2012] [Indexed: 12/14/2022]
Abstract
Gene expression profiling had revealed that TGF-β superfamily type I receptor (also known as activin receptor-like kinase-1, ALK1) and TGFβR2 (TGF-β type II receptor) were down-regulated in nasopharyngeal carcinoma (NPC) (P < 0.05, respectively). However, no study with significantly large clinical samples to address the relevance of ALK1 and TGFβR2 in NPC progression or in patient outcomes has been reported. This study aims to assess the possible correlations of ALK1 and TGFβR2 expression with NPC progression and their potential prognostic predictive ability in NPC outcomes. ALK1 and TGFβR2 mRNA and protein levels were detected by qRT-PCR and NPC tissue microarray (TMA), which included 742 tissue cores. Both mRNA and protein levels of ALK1 and TGFβR2 were significantly lower in the cancer tissues compared with the non-cancerous tissues (P < 0.05). Epstein-Barr virus small RNA (EBER-1) hybridization signals in NPC showed significant associations with ALK1 and TGFβR2 proteins (P = 0.000 and 0.003, respectively). In the final logistic regression analysis model, the abnormal expression of ALK1 and TGFβR2 were found to be independent contributors to nasopharyngeal carcinogenesis (P = 0.000 and 0.000, respectively). A survival analysis revealed that ALK1 (Disease Free Survival (DFS): P = 0.002, Overall Survival (OS): P = 0.007) and TGFβR2 (DFS: P = 0.072, OS: P = 0.045) could predict the prognosis of NPC patients. The positive expression of ALK1 and TGFβR2 were independent risk factors for DFS and OS in multivariate analyses (DFS: P = 0.001 and 0.420, respectively; OS: P = 0.018 and 0.047, respectively). These results suggest that ALK1 and TGFβR2 may be useful prognostic biomarkers in NPC.
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Affiliation(s)
- Wenling Zhang
- Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha 410013, China
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Giordano A, Romano S, Monaco M, Sorrentino A, Corcione N, Di Pace AL, Ferraro P, Nappo G, Polimeno M, Romano MF. Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells. Am J Physiol Heart Circ Physiol 2011; 302:H135-42. [PMID: 22058159 DOI: 10.1152/ajpheart.00490.2011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although considered promising for use in drug-eluting stents (DES), tacrolimus failed clinically. Tacrolimus inhibits growth factor production but can also act as a growth factor on vascular smooth muscle cells (VSMC). This unexpected proliferative stimulus could reverse the beneficial effects of the drug on restenosis. We hypothesized that tacrolimus' association with statins, which lower cholesterol and impair cell proliferation, could restore tacrolimus' beneficial effect by abrogating the aberrant proliferative stimulus. Additionally, since maintenance of endothelial function represents a challenge for new-generation DES, we investigated the combined effect of tacrolimus and atorvastatin on endothelial cells. Human VSMC and umbilical vein endothelial cells (HUVEC) were incubated with 100 nM tacrolimus and increasing doses of atorvastatin (0-3.0 μM). Atorvastatin plus tacrolimus dose-dependently inhibited VSMC proliferation. The percentage of cells incorporating 5-bromo-2'-deoxyuridine (BrdU) in their DNA was 49 ± 14% under basal conditions, 62 ± 15% (P = 0.01) with tacrolimus, 40 ± 22% with 3 μM atorvastatin, and 30 ± 7% (P < 0.05) with 3 μM atorvastatin plus tacrolimus. Atorvastatin downregulated β-catenin, Erk1 and Erk2, and cyclin B in tacrolimus-stimulated VSMC. In contrast, atorvastatin plus tacrolimus did not affect proliferation of endothelial cells. The percentage of HUVEC incorporating BrdU in their DNA was 47 ± 8% under basal conditions, 58 ± 6% (P = 0.01) with tacrolimus, 45 ± 4% with 3 μM atorvastatin, and 49 ± 1% with 3 μM atorvastatin plus tacrolimus. Both agents stimulated endoglin production by HUVEC. Taken together, these results suggest that, when combined with tacrolimus, atorvastatin exerts a dose-dependent antiproliferative effect on VSMC. In contrast, atorvastatin acts in concert with tacrolimus in HUVEC to stimulate production of endoglin, a factor that has an important role in endothelial repair. Our study supports the conclusion that prevention of postcoronary in-stent restenosis and late thrombosis may benefit of concomitant association of tacrolimus and high doses of atorvastatin.
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Affiliation(s)
- Arturo Giordano
- Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy
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