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Updated: Aug 10, 2026
Inducing Myointimal Hyperplasia Versus Atherosclerosis in Mice: An Introduction of Two Valid Models
Published on: May 14, 2014
Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury
Gustavo E Crespo-Avilan1, Sauri Hernandez-Resendiz2, Chrishan J Ramachandra2
1Department of Biochemistry, Medical Faculty, Justus Liebig-University, Giessen, Germany; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
Background And Aims:
New treatments are needed to prevent 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-like macrophages, and decreased plaque inflammation, endothelial activation, and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from a pro-inflammatory M1-like to an anti-inflammatory M2-like phenotype, reduced monocyte chemotaxis and migration to CCL2 and macrophage colony stimulating factor (M-CSF) and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-type-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-like phenotype by inhibiting oxidative phosphorylation and attenuating the increase in succinate levels and correcting the decreased levels of arginine and citrulline.
Conclusions:
We report that treatment with Mdivi-1 inhibits 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.
Insights
Mitochondrial division inhibitor-1 (Mdivi-1) reduces neointimal hyperplasia by reprogramming macrophages to an anti-inflammatory state. This offers a potential new therapy for preventing restenosis after angioplasty and stenting in patients with coronary and peripheral artery disease.
Area of Science:
- Vascular Biology
- Immunometabolism
- Mitochondrial Dynamics
Background:
- Neointimal hyperplasia drives restenosis after angioplasty and stenting in coronary artery disease (CAD) and peripheral artery disease (PAD).
- Current treatments lack efficacy in preventing post-vascular injury neointimal hyperplasia.
- Targeting macrophage phenotype offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate if modulating mitochondrial function with mitochondrial division inhibitor-1 (Mdivi-1) can prevent neointimal hyperplasia.
- To determine if Mdivi-1 reprograms macrophages from a pro-inflammatory to an anti-inflammatory phenotype.
- To assess the therapeutic potential of Mdivi-1 for CAD and PAD patients.
Main Methods:
- In vivo Mdivi-1 treatment in Apoe-/- mice subjected to carotid-wire injury.
- In vitro Mdivi-1 treatment of human THP-1 macrophages and M1-type macrophages.
- Analysis of neointimal hyperplasia, macrophage phenotype, inflammation, and metabolic pathways.
Main Results:
- Mdivi-1 significantly reduced neointimal hyperplasia by 68% in mice.
- Mdivi-1 treatment shifted macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype.
- Mdivi-1 inhibited oxidative phosphorylation and altered metabolite levels (succinate, arginine, citrulline) in M1 macrophages.
Conclusions:
- Mdivi-1 inhibits post-vascular injury neointimal hyperplasia.
- Metabolic reprogramming of macrophages to an anti-inflammatory phenotype is a key mechanism.
- Mdivi-1 demonstrates therapeutic potential for preventing restenosis in CAD and PAD.
