Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis
Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemog...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/4763 |
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| author | Janae Gonzales Kelsey Holbert Kamryn Czysz Joseph George Caroline Fernandes Dustin R. Fraidenburg |
| author_facet | Janae Gonzales Kelsey Holbert Kamryn Czysz Joseph George Caroline Fernandes Dustin R. Fraidenburg |
| author_sort | Janae Gonzales |
| collection | DOAJ |
| description | Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states. |
| first_indexed | 2024-03-10T04:05:52Z |
| format | Article |
| id | doaj.art-041db7794689472f9dc8013aa9d2a5fe |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:05:52Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-041db7794689472f9dc8013aa9d2a5fe2023-11-23T08:21:55ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01239476310.3390/ijms23094763Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic HemolysisJanae Gonzales0Kelsey Holbert1Kamryn Czysz2Joseph George3Caroline Fernandes4Dustin R. Fraidenburg5Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, University of Wisconsin, Madison, WI 53792, USADepartment of Chemistry, University of Denver, Denver, CO 80208, USADepartment of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USAPulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states.https://www.mdpi.com/1422-0067/23/9/4763endothelial dysfunctionendothelial to mesenchymal transitionpulmonary hypertensionhemolysis |
| spellingShingle | Janae Gonzales Kelsey Holbert Kamryn Czysz Joseph George Caroline Fernandes Dustin R. Fraidenburg Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis International Journal of Molecular Sciences endothelial dysfunction endothelial to mesenchymal transition pulmonary hypertension hemolysis |
| title | Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis |
| title_full | Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis |
| title_fullStr | Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis |
| title_full_unstemmed | Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis |
| title_short | Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis |
| title_sort | hemin induced endothelial dysfunction and endothelial to mesenchymal transition in the pathogenesis of pulmonary hypertension due to chronic hemolysis |
| topic | endothelial dysfunction endothelial to mesenchymal transition pulmonary hypertension hemolysis |
| url | https://www.mdpi.com/1422-0067/23/9/4763 |
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