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DN200434 Inhibits Vascular Smooth Muscle Cell Proliferation and Prevents Neointima Formation in Mice after Carotid
Sudeep Kumar1,2, Jonghwa Jin2, Hyeon Young Park3
1Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Korea.
Backgruound:
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contributes to the development of occlusive vascular diseases, requires elevated mitochondrial oxidative phosphorylation to meet the increased requirements for energy and anabolic precursors. Therefore, therapeutic strategies based on blockade of mitochondrial oxidative phosphorylation are considered promising for treatment of occlusive vascular diseases. Here, we investigated whether DN200434, an orally available estrogen receptor-related gamma inverse agonist, inhibits proliferation and migration of VSMCs and neointima formation by suppressing mitochondrial oxidative phosphorylation.
Methods:
VSMCs were isolated from the thoracic aortas of 4-week-old Sprague-Dawley rats. Oxidative phosphorylation and the cell cycle were analyzed in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using a Seahorse XF-24 analyzer and flow cytometry, respectively. A model of neointimal hyperplasia was generated by ligating the left common carotid artery in male C57BL/6J mice.
Results:
DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 activity and consequently suppressed FBS- or PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Furthermore, DN200434 reduced carotid artery ligation-induced neointima formation in mice.
Conclusion:
Our data suggest that DN200434 is a therapeutic option to prevent the progression of atherosclerosis.
Insights
DN200434, an estrogen receptor-related gamma inverse agonist, inhibits vascular smooth muscle cell proliferation and migration by suppressing mitochondrial oxidative phosphorylation. This compound shows promise for preventing atherosclerosis progression.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Physiology
- Pharmacology
Background:
- Vascular smooth muscle cell (VSMC) proliferation and migration are key drivers of occlusive vascular diseases.
- Elevated mitochondrial oxidative phosphorylation fuels VSMC growth and is a potential therapeutic target.
- Estrogen receptor-related gamma inverse agonists are being explored for cardiovascular applications.
Purpose of the Study:
- To investigate the effects of DN200434, an estrogen receptor-related gamma inverse agonist, on VSMC proliferation, migration, and neointima formation.
- To determine if DN200434 exerts its effects by suppressing mitochondrial oxidative phosphorylation.
- To evaluate DN200434 as a potential therapeutic agent for occlusive vascular diseases.
Main Methods:
- VSMCs were isolated from rats and stimulated with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF).
- Mitochondrial oxidative phosphorylation and cell cycle progression were analyzed using Seahorse XF-24 and flow cytometry.
- Neointimal hyperplasia was induced in mice via carotid artery ligation.
Main Results:
- DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 (mTORC1) activity.
- DN200434 suppressed FBS- or PDGF-stimulated VSMC proliferation, migration, and cell cycle progression.
- DN200434 significantly reduced neointima formation in a mouse model.
Conclusions:
- DN200434 effectively inhibits VSMC proliferation and migration by targeting mitochondrial oxidative phosphorylation.
- DN200434 demonstrates therapeutic potential for preventing atherosclerosis and related occlusive vascular diseases.
- The findings support DN200434 as a promising candidate for treating atherosclerosis.
