Kim Ji-Hyun, Bae Kwi-Hyun, Byun Jun-Kyu, Lee Sungwoo, Kim Jung-Guk, Lee In Kyu, Jung Gwon-Soo, Lee You Mie, Park Keun-Gyu
Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, South Korea.
Biochem Biophys Res Commun. 2017 Oct 7;492(1):41-47. doi: 10.1016/j.bbrc.2017.08.041. Epub 2017 Aug 14.
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.
血管平滑肌细胞（VSMC）的增殖和迁移与动脉粥样硬化的发病机制有关。有氧糖酵解增加是包括癌症和免疫细胞在内的细胞表型的关键特征。然而，有氧糖酵解在VSMC致动脉粥样硬化表型中的作用仍 largely 未知。在此，我们研究了糖酵解关键酶乳酸脱氢酶 A（LDHA）在VSMC增殖和迁移中的作用。用胎牛血清（FBS）或血小板衍生生长因子（PDGF）激活原代大鼠VSMC可增加其增殖和迁移、糖酵解活性以及LDHA的表达。伤口愈合和transwell迁移试验表明，小干扰RNA介导的LDHA敲低和草氨酸对LDHA的药理学抑制均有效抑制了VSMC的增殖和迁移。草氨酸对LDHA活性的抑制降低了PDGF刺激的葡萄糖摄取、乳酸产生和ATP产生。综上所述，本研究表明，PDGF或FBS刺激的VSMC中糖酵解增强在其增殖和迁移中起重要作用，并表明LDHA是预防动脉粥样硬化和再狭窄过程中血管腔狭窄的潜在治疗靶点。
