Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation.

Hyeon Young Park,Jung-Guk Kim,Seunghyeong Lee,Keun-Gyu Park,Jonghwa Jin,Yeon-Kyung Choi,Mi-Jin Kim,Sungwoo Lee

doi:10.3390/ijms22115602

Abstract

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

Highlights

Vascular smooth muscle cells (VSMCs) are the major component of the vasculature and help to maintain vessel tone, the bloodstream, and blood pressure [1]
Given that glutamine contributes to TCA intermediates and DON targets mitochondria in cancer research [25], we first measured the oxygen consumption ratio (OCR) in DONtreated VSMCs stimulated with Fetal Bovine Serum (FBS) or Platelet-Derived Growth Factor (PDGF)
Given that mTORC1 increases glucose uptake and glycolysis by upregulating hypoxia-inducible factor-1α (HIF-1α) [27], we investigated whether the DON-induced suppression of mTORC1 inhibits glycolysis in VSMCs

Summary

Introduction

Vascular smooth muscle cells (VSMCs) are the major component of the vasculature and help to maintain vessel tone, the bloodstream, and blood pressure [1]. Phenotypic switching of VSMCs in response to various physiological and pathological factors has long been considered of fundamental importance for proliferation and migration of VSMCs and pathological intima formation, which leads to the development of various vascular diseases including atherosclerosis, transplant vasculopathy, and pulmonary hypertension [4,5]. VSMCs undergo metabolic reprogramming such as enhancement of aerobic glycolysis to support their increased energy requirements and biosynthesis of macromolecules during rapid proliferation and contractile switching [6,7,8]. Increasing evidence shows that enhanced glycolysis and glutaminolysis contribute to proliferation, migration, and collagen synthesis of vascular cells [15,16]. Therapeutic strategies based on the blockade of aerobic glycolysis or glutamine metabolism may be effective for treatment of occlusive vascular diseases

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Results

Conclusion