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Title: Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration

Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) have been implicated in the pathogenesis of atherosclerosis. Increased aerobic glycolysis is a key feature of cellular phenotypes including cancer and immune cells. However, the role of aerobic glycolysis in the atherogenic phenotype of VSMCs remains largely unknown. Here, we investigated the role of lactate dehydrogenase-A (LDHA), which is a key enzyme for glycolysis, in the proliferation and migration of VSMCs. Activation of primary rat VSMCs with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF) increased their proliferation and migration, glycolytic activity, and expression of LDHA. Wound healing and transwell migration assays demonstrated that small interfering RNA-mediated knockdown of LDHA and pharmacological inhibition of LDHA by oxamate both effectively inhibited VSMC proliferation and migration. Inhibition of LDHA activity by oxamate reduced PDGF-stimulated glucose uptake, lactate production, and ATP production. Taken together, this study shows that enhanced glycolysis in PDGF- or FBS-stimulated VSMCs plays an important role in their proliferation and migration and suggests that LDHA is a potential therapeutic target to prevent vessel lumen constriction during the course of atherosclerosis and restenosis. - Highlights: • LDHA levels were upregulated in proliferative and migratory VSMCs. • Inhibition of LDHA suppressedmore » growth factor-stimulated VSMC proliferation/migration. • Inhibition of LDHA reduced growth factor-stimulated glycolysis in VSMCs. • Targeting LDHA has a potential to treat excessive VSMC proliferation and migration.« less

Authors:
;  [1];  [2];  [3];  [1];  [1];  [1];
  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu (Korea, Republic of)
  2. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu (Korea, Republic of)
  3. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu (Korea, Republic of)
Publication Date:
OSTI Identifier:
22719100
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 492; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARTERIOSCLEROSIS; ATP; CATTLE; CELL PROLIFERATION; GLUCOSE; GLYCOLYSIS; GROWTH FACTORS; HEALING; INHIBITION; LACTATE DEHYDROGENASE; LACTATES; MUSCLES; NEOPLASMS; PATHOGENESIS; RATS; RNA; WOUNDS

Citation Formats

Kim, Ji-Hyun, Bae, Kwi-Hyun, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Byun, Jun-Kyu, Lee, Sungwoo, Kim, Jung-Guk, Lee, In Kyu, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Jung, Gwon-Soo, Lee, You Mie, E-mail: lym@knu.ac.kr, and others, and. Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.08.041.
Kim, Ji-Hyun, Bae, Kwi-Hyun, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Byun, Jun-Kyu, Lee, Sungwoo, Kim, Jung-Guk, Lee, In Kyu, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Jung, Gwon-Soo, Lee, You Mie, E-mail: lym@knu.ac.kr, & others, and. Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration. United States. doi:10.1016/J.BBRC.2017.08.041.
Kim, Ji-Hyun, Bae, Kwi-Hyun, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Byun, Jun-Kyu, Lee, Sungwoo, Kim, Jung-Guk, Lee, In Kyu, Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Jung, Gwon-Soo, Lee, You Mie, E-mail: lym@knu.ac.kr, and others, and. Sat . "Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration". United States. doi:10.1016/J.BBRC.2017.08.041.
@article{osti_22719100,
title = {Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration},
author = {Kim, Ji-Hyun and Bae, Kwi-Hyun and Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu and Byun, Jun-Kyu and Lee, Sungwoo and Kim, Jung-Guk and Lee, In Kyu and Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu and Jung, Gwon-Soo and Lee, You Mie, E-mail: lym@knu.ac.kr and others, and},
abstractNote = {The proliferation and migration of vascular smooth muscle cells (VSMCs) have been implicated in the pathogenesis of atherosclerosis. Increased aerobic glycolysis is a key feature of cellular phenotypes including cancer and immune cells. However, the role of aerobic glycolysis in the atherogenic phenotype of VSMCs remains largely unknown. Here, we investigated the role of lactate dehydrogenase-A (LDHA), which is a key enzyme for glycolysis, in the proliferation and migration of VSMCs. Activation of primary rat VSMCs with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF) increased their proliferation and migration, glycolytic activity, and expression of LDHA. Wound healing and transwell migration assays demonstrated that small interfering RNA-mediated knockdown of LDHA and pharmacological inhibition of LDHA by oxamate both effectively inhibited VSMC proliferation and migration. Inhibition of LDHA activity by oxamate reduced PDGF-stimulated glucose uptake, lactate production, and ATP production. Taken together, this study shows that enhanced glycolysis in PDGF- or FBS-stimulated VSMCs plays an important role in their proliferation and migration and suggests that LDHA is a potential therapeutic target to prevent vessel lumen constriction during the course of atherosclerosis and restenosis. - Highlights: • LDHA levels were upregulated in proliferative and migratory VSMCs. • Inhibition of LDHA suppressed growth factor-stimulated VSMC proliferation/migration. • Inhibition of LDHA reduced growth factor-stimulated glycolysis in VSMCs. • Targeting LDHA has a potential to treat excessive VSMC proliferation and migration.},
doi = {10.1016/J.BBRC.2017.08.041},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 492,
place = {United States},
year = {2017},
month = {10}
}