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A multifaceted investigation into molecular associations of chronic thromboembolic pulmonary hypertension pathogenesis
PURPOSE: Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019411/ https://www.ncbi.nlm.nih.gov/pubmed/32110389 http://dx.doi.org/10.1177/2048004020906994 |
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author | Halliday, Stephen J Matthews, Daniel T Talati, Megha H Austin, Eric D Su, Yan R Absi, Tarek S Fortune, Niki L Gailani, David Matafonov, Anton West, James D Hemnes, Anna R |
author_facet | Halliday, Stephen J Matthews, Daniel T Talati, Megha H Austin, Eric D Su, Yan R Absi, Tarek S Fortune, Niki L Gailani, David Matafonov, Anton West, James D Hemnes, Anna R |
author_sort | Halliday, Stephen J |
collection | PubMed |
description | PURPOSE: Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been associated with chronic thromboembolic pulmonary hypertension, but molecular mechanisms underlying this disease are poorly understood. We sought to characterize the molecular and functional features associated with chronic thromboembolic pulmonary hypertension using a multifaceted approach. METHODS: We utilized functional assays to compare clot lysis times between chronic thromboembolic pulmonary hypertension patients and multiple controls. We then performed immunohistochemical characterization of tissue from chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and healthy controls, and examined RNA expression patterns of cultured lymphocytes and pulmonary arterial specimens. We then confirmed RNA expression changes using immunohistochemistry, immunofluorescence, and Western blotting in pulmonary arterial tissue. RESULTS: Clot lysis times in chronic thromboembolic pulmonary hypertension patients are similar to multiple controls. Chronic thromboembolic pulmonary hypertension endarterectomized tissue has reduced expression of both smooth muscle and endothelial cell markers. RNA expression profiles in pulmonary arteries and peripheral blood lymphocytes identified differences in RNA transcript levels related to inflammation and growth factor signaling, which we confirmed using immunohistochemistry. Gene expression data also suggested significant alterations in metabolic pathways, and immunofluorescence and Western blot experiments confirmed that unglycosylated CD36 and adiponectin expression were increased in chronic thromboembolic pulmonary hypertension versus controls. CONCLUSIONS: Our data do not support impaired clot lysis underlying chronic thromboembolic pulmonary hypertension, but did demonstrate distinct molecular patterns present both in peripheral blood and in pathologic specimens of chronic thromboembolic pulmonary hypertension patients suggesting that altered metabolism may play a role in chronic thromboembolic pulmonary hypertension pathogenesis. |
format | Online Article Text |
id | pubmed-7019411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-70194112020-02-27 A multifaceted investigation into molecular associations of chronic thromboembolic pulmonary hypertension pathogenesis Halliday, Stephen J Matthews, Daniel T Talati, Megha H Austin, Eric D Su, Yan R Absi, Tarek S Fortune, Niki L Gailani, David Matafonov, Anton West, James D Hemnes, Anna R JRSM Cardiovasc Dis Research Paper PURPOSE: Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been associated with chronic thromboembolic pulmonary hypertension, but molecular mechanisms underlying this disease are poorly understood. We sought to characterize the molecular and functional features associated with chronic thromboembolic pulmonary hypertension using a multifaceted approach. METHODS: We utilized functional assays to compare clot lysis times between chronic thromboembolic pulmonary hypertension patients and multiple controls. We then performed immunohistochemical characterization of tissue from chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and healthy controls, and examined RNA expression patterns of cultured lymphocytes and pulmonary arterial specimens. We then confirmed RNA expression changes using immunohistochemistry, immunofluorescence, and Western blotting in pulmonary arterial tissue. RESULTS: Clot lysis times in chronic thromboembolic pulmonary hypertension patients are similar to multiple controls. Chronic thromboembolic pulmonary hypertension endarterectomized tissue has reduced expression of both smooth muscle and endothelial cell markers. RNA expression profiles in pulmonary arteries and peripheral blood lymphocytes identified differences in RNA transcript levels related to inflammation and growth factor signaling, which we confirmed using immunohistochemistry. Gene expression data also suggested significant alterations in metabolic pathways, and immunofluorescence and Western blot experiments confirmed that unglycosylated CD36 and adiponectin expression were increased in chronic thromboembolic pulmonary hypertension versus controls. CONCLUSIONS: Our data do not support impaired clot lysis underlying chronic thromboembolic pulmonary hypertension, but did demonstrate distinct molecular patterns present both in peripheral blood and in pathologic specimens of chronic thromboembolic pulmonary hypertension patients suggesting that altered metabolism may play a role in chronic thromboembolic pulmonary hypertension pathogenesis. SAGE Publications 2020-02-13 /pmc/articles/PMC7019411/ /pubmed/32110389 http://dx.doi.org/10.1177/2048004020906994 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Paper Halliday, Stephen J Matthews, Daniel T Talati, Megha H Austin, Eric D Su, Yan R Absi, Tarek S Fortune, Niki L Gailani, David Matafonov, Anton West, James D Hemnes, Anna R A multifaceted investigation into molecular associations of chronic thromboembolic pulmonary hypertension pathogenesis |
title | A multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
title_full | A multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
title_fullStr | A multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
title_full_unstemmed | A multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
title_short | A multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
title_sort | multifaceted investigation into molecular associations of chronic
thromboembolic pulmonary hypertension pathogenesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019411/ https://www.ncbi.nlm.nih.gov/pubmed/32110389 http://dx.doi.org/10.1177/2048004020906994 |
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