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The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia. | LitMetric

AI Article Synopsis

  • Restenosis is a major issue for people with peripheral artery diseases, primarily caused by intimal hyperplasia (IH), where vascular smooth muscle cells (VSMCs) excessively grow in the arteries, leading to health issues and repeated treatments.* -
  • The enzyme 6-Phosphogluconate dehydrogenase (6PGD) was found to be significantly increased in diseased coronary arteries and plays an important role in the hyperproliferation and migration of VSMCs during the process of phenotypic switching.* -
  • The study reveals that targeting 6PGD could provide a new therapeutic approach for addressing IH and restenosis by using specific inhibitors that reduce its activity, showing promise in

Article Abstract

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 , 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420449PMC
http://dx.doi.org/10.1016/j.jvssci.2024.100214DOI Listing

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