Mitochondrial division inhibitor 1 (mdivi-1) as a potential pharmacological strategy to prevent vascular restenosis

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore National Medical Research Council Background New treatments are needed to prevent post-angioplasty and stent restenosis in coronary artery disease (CAD) and peripheral arterial disease (PAD) patients. Accumulated findings have shown that mitochondrial dysfunction is involved in the pathophysiology mechanisms underlying several cardiovascular conditions, however, in the scenario of vascular remodelling after injury, the role of mitochondrial dynamics is not completely understood. Purpose In this study, we investigate the effect of mdivi-1 on neointimal hyperplasia and plaque development in a wire-induced endothelial injury animal model.­ Methods Using ApoE-/- mice on a background of hyperlipidaemia, we investigated weather in vivo administration of mdivi-1 (1.2mg/kg/d) could reduce atherosclerotic plaque volume, plaque complexity and inflammation in a carotid-wire injury model of neointimal hyperplasia. Also, THP-1 monocytes (T-M) and THP-1-derived Macrophages (T-DM) were stimulated in vitro with LPS + IFN-gamma to induce M1 polarization and then subjected to gene expression and protein analysis in the presence or absence of mdivi-1 (50µM). Transmigration and 3D chemotaxis assays were performed in T-M cells and Human peripheral blood monocytes, to evaluate the effect of mdivi-1 on cell migration in response to M-CSF and MCP-1. Finally, we investigated the effects of Mdivi-1 on mitochondrial respiration using Seahorse assay in T-M and T-DM. Results In vivo treatment with mdivi-1 reduced neointimal hyperplasia by 37% when compared to control, and was associated with a significant decrease of vascular smooth muscle cells and macrophages cell numbers, as well as reduction of the pro-inflammatory mediators TNF-α and ICAM-1 in the plaque. In vitro M1 polarization of T-M and T-DM induced both up-regulation and production of pro-inflammatory mediators and mdivi-1 significantly suppressed this effects. In addition, monocyte chemotaxis response to M-CSF and MCP-1 was significantly reduced in the presence of mdivi-1. Lastly, mdivi-1 reduced oxygen consumption rate in T-M and T-DM, and prevented M1-cell polarization. Conclusions We show that mdivi-1 significantly reduces vessel wall thickness, neointimal hyperplasia, monocyte recruitment, and inflammation after vascular endothelial injury, positioning Mdivi-1 as a potential pharmacological strategy to reduce restenosis following angioplasty and stenting in CAD and PAD patients.