The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia
Background: Restenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperp...
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Elsevier
2024-01-01
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| Series: | JVS - Vascular Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666350324000257 |
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| author | Amy L. Lu Li Yin, PhD Yitao Huang, BS Zain Husain Islam Rohan Kanchetty Campbell Johnston Kaijie Zhang, MD Xiujie Xie, PhD Ki Ho Park, PhD Charles E. Chalfant, PhD Bowen Wang, PhD |
| author_facet | Amy L. Lu Li Yin, PhD Yitao Huang, BS Zain Husain Islam Rohan Kanchetty Campbell Johnston Kaijie Zhang, MD Xiujie Xie, PhD Ki Ho Park, PhD Charles E. Chalfant, PhD Bowen Wang, PhD |
| author_sort | Amy L. Lu |
| collection | DOAJ |
| description | Background: Restenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperproliferative and migratory vascular smooth muscle cell (VSMC) accumulate excessively in the tunica intima. 6-Phosphogluconate dehydrogenase (6PGD), sometimes referred to as PGD, is one of the critical enzymes in pentose phosphate pathway (PPP). In this study, we sought to probe whether 6PGD is aberrantly regulated in IH and contributes to VSMC phenotypic switching. Methods: We used clinical specimens of diseased human coronary arteries with IH lesions and observed robust upregulation of 6PGD at protein level in both the medial and intimal layers in comparison with healthy arterial segments. Results: 6PGD activity and protein expression were profoundly stimulated upon platelet-derived growth factor-induced VSMC phenotypic switching. Using gain-of-function (dCas9-mediated transcriptional activation) and loss-of-function (small interfering RNA-mediated) silencing, we were able to demonstrate the pathogenic role of 6PGD in driving VSMC hyperproliferation, migration, dedifferentiation, and inflammation. Finally, we conducted a rat model of balloon angioplasty in the common carotid artery, with Pluronic hydrogel-assisted perivascular delivery of Physcion, a selective 6PGD inhibitor with poor systemic bioavailability, and observed effective mitigation of IH. Conclusions: We contend that aberrant 6PGD expression and activity—indicative of a metabolic shift toward pentose phosphate pathway—could serve as a new disease-driving mechanism and, hence, an actionable target for the development of effective new therapies for IH and restenosis after endovascular interventions. |
| format | Article |
| id | doaj-art-b2148e7a23114b61bcc2303d6ebfd0c0 |
| institution | OA Journals |
| issn | 2666-3503 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
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| series | JVS - Vascular Science |
| spelling | doaj-art-b2148e7a23114b61bcc2303d6ebfd0c02025-08-20T02:35:29ZengElsevierJVS - Vascular Science2666-35032024-01-01510021410.1016/j.jvssci.2024.100214The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasiaAmy L. Lu0Li Yin, PhD1Yitao Huang, BS2Zain Husain Islam3Rohan Kanchetty4Campbell Johnston5Kaijie Zhang, MD6Xiujie Xie, PhD7Ki Ho Park, PhD8Charles E. Chalfant, PhD9Bowen Wang, PhD10Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA; Division of Hematology & Oncology, Department of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA; Department of Vascular Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang, China; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, ILDepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA; Department of Vascular Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang, China; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, ILDivision of Hematology & Oncology, Department of Medicine, University of Virginia, Charlottesville, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VADivision of Hematology & Oncology, Department of Medicine, University of Virginia, Charlottesville, VA; Research Service, Richmond Veterans Administration Medical Center, Richmond, VADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL; Correspondence: Bowen Wang, PhD, Department of Surgery, Feinberg School of Medicine, Northwestern University, 300 E Superior 2-709, Chicago, IL 60611Background: Restenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperproliferative and migratory vascular smooth muscle cell (VSMC) accumulate excessively in the tunica intima. 6-Phosphogluconate dehydrogenase (6PGD), sometimes referred to as PGD, is one of the critical enzymes in pentose phosphate pathway (PPP). In this study, we sought to probe whether 6PGD is aberrantly regulated in IH and contributes to VSMC phenotypic switching. Methods: We used clinical specimens of diseased human coronary arteries with IH lesions and observed robust upregulation of 6PGD at protein level in both the medial and intimal layers in comparison with healthy arterial segments. Results: 6PGD activity and protein expression were profoundly stimulated upon platelet-derived growth factor-induced VSMC phenotypic switching. Using gain-of-function (dCas9-mediated transcriptional activation) and loss-of-function (small interfering RNA-mediated) silencing, we were able to demonstrate the pathogenic role of 6PGD in driving VSMC hyperproliferation, migration, dedifferentiation, and inflammation. Finally, we conducted a rat model of balloon angioplasty in the common carotid artery, with Pluronic hydrogel-assisted perivascular delivery of Physcion, a selective 6PGD inhibitor with poor systemic bioavailability, and observed effective mitigation of IH. Conclusions: We contend that aberrant 6PGD expression and activity—indicative of a metabolic shift toward pentose phosphate pathway—could serve as a new disease-driving mechanism and, hence, an actionable target for the development of effective new therapies for IH and restenosis after endovascular interventions.http://www.sciencedirect.com/science/article/pii/S2666350324000257RestenosisIntimal hyperplasiaSmooth muscle cellPeripheral vascular diseasePentose phosphate pathway |
| spellingShingle | Amy L. Lu Li Yin, PhD Yitao Huang, BS Zain Husain Islam Rohan Kanchetty Campbell Johnston Kaijie Zhang, MD Xiujie Xie, PhD Ki Ho Park, PhD Charles E. Chalfant, PhD Bowen Wang, PhD The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia JVS - Vascular Science Restenosis Intimal hyperplasia Smooth muscle cell Peripheral vascular disease Pentose phosphate pathway |
| title | The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia |
| title_full | The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia |
| title_fullStr | The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia |
| title_full_unstemmed | The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia |
| title_short | The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia |
| title_sort | role of 6 phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty induced intimal hyperplasia |
| topic | Restenosis Intimal hyperplasia Smooth muscle cell Peripheral vascular disease Pentose phosphate pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2666350324000257 |
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