The Mitochondrial Fission Regulator Drp-1 (Dynamin-related protein-1) as a Novel Therapeutic Target to Prevent Atherosclerosis

Background and aims: New treatments are needed to prevent the neointimal hyperplasia that contributes to post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) and peripheral arterial disease (PAD). We investigated whether modulating mitochondrial function using mitochondrial division inhibitor-1 (Mdivi-1) could reduce post-vascular injury neointimal hyperplasia by metabolic reprogramming of macrophages from a pro-inflammatory to anti-inflammatory phenotype. Methods and results: In vivo Mdivi-1 treatment of Apoe-/- mice fed a high-fat diet and subjected to carotid-wire injury decreased neointimal hyperplasia by 68%, reduced numbers of plaque vascular smooth muscle cells and pro-inflammatory M1-macrophages, and decreased plaque inflammation, endothelial activation and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, reduced monocyte chemotaxis and migration to MCP-1 and M-CSF and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-phenotype by inhibiting oxidative phosphorylation. Conclusions: This study shows that treatment with Mdivi-1 inhibited post-vascular injury neointimal hyperplasia by metabolic reprogramming macrophages towards an anti-inflammatory phenotype thereby highlighting the therapeutic potential of Mdivi-1 for preventing neointimal hyperplasia and restenosis following angioplasty and stenting in CAD and PAD patients.

Collections

Dissertationen/Habilitationen

Full item page

The Mitochondrial Fission Regulator Drp-1 (Dynamin-related protein-1) as a Novel Therapeutic Target to Prevent Atherosclerosis

Files

Date

Authors

Advisors/Reviewers

Further Contributors

Contributing Institutions

Publisher

Journal Title

Journal ISSN

Volume Title

Publisher

License

Quotable link

Abstract

Link to publications or other datasets

Description

Notes

Original publication in

Original publication in

Anthology

Collections

URI of original publication

Forschungsdaten

Series

Citation