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

Abstract

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.