DN200434 Inhibits Vascular Smooth Muscle Cell Proliferation and Prevents Neointima Formation in Mice after Carotid Artery Ligation

Background: 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,...

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Published inEndocrinology and metabolism (Seoul) Vol. 37; no. 5; pp. 800 - 809
Main Authors Sudeep Kumar, Jonghwa Jin, Hyeon Young Park, Mi-jin Kim, Jungwook Chin, Sungwoo Lee, Jina Kim, Jung-guk Kim, Yeon-kyung Choi, Keun-gyu Park
Format Journal Article
LanguageKorean
Published 대한내분비학회 31.10.2022
Subjects
Estrogen-related receptor gamma protein
Mechanistic target of rapamycin complex 1
Muscle
Neointima
Oxidative phosphorylation
smooth
vascular
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Summary:Background: 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.
Bibliography:The Korean Society of Endocrinology
ISSN:2093-596X