Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration
Introduction
Characteristic metabolic reprogramming in proliferative cells has emerged as a crucial player in determination of their phenotypes and signal transduction processes [1]. Although mainly studied in cancer models, growth factors influence cell proliferation by altering intracellular metabolism; therefore, several key enzymes that regulate glycolysis or mitochondrial respiration have been proposed as targets for the treatment of cancer [2], [3]. A Warburg-like increase in the glycolytic rate also appears to be inherent to non-malignant cells such as immune and skeletal muscle cells [4], [5], [6]. Several recent studies suggested that metabolic reprograming in vascular smooth muscle cells (VSMCs) participates in the complex regulation of their proliferation and migration [7], [8], [9].
VSMC proliferation and migration are involved in physiological processes such as development, wound healing, and angiogenesis [10]. However, once tissue repair is complete, the continuation of VSMC proliferation and migration due to excessive mitogens such as growth factors in the cellular microenvironment induces pathogenic vessel lumen constriction during the course of atherosclerosis and restenosis [11], [12]. For this reason, extensive research has focused on elucidating the intracellular mechanisms involved in the regulation of VSMC proliferation and migration [13], [14], [15]. Recent studies showed that enhanced glycolysis may be required for platelet-derived growth factor (PDGF)-induced VSMC proliferation, supported by increased glycolytic enzyme expression, lactate production, and glucose utilization [7], [8].
Modulating VSMC metabolism via anti-glycolytic therapies may be a means to treat atherosclerosis and restenosis because increased glycolysis is associated with the proliferation of VSMCs and cancer cells [8]. The enzyme lactate dehydrogenase-A (LDHA) is of particular interest because it catalyzes the nicotinamide adenine dinucleotide-dependent reduction of pyruvate to lactate, an essential step for regenerating nicotinamide adenine dinucleotide, which is needed to maintain glycolysis and other metabolic activities [16], [17], [18]. However, the role of LDHA in VSMC proliferation and migration has not been investigated. Therefore, we aimed to examine the role of LDHA in the proliferation and migration of VSMCs.
Section snippets
Immunohistochemical staining of balloon-injured rat carotid arteries
The rat carotid artery balloon-injury method was described previously [19]. Rat arterial tissue was fixed in 4% paraformaldehyde and embedded in paraffin. For immunohistochemical staining, paraffinized aorta sections were deparaffinized with xylene and ethanol. Endogenous peroxidase was blocked by treatment with 3% H2O2 for 15 min and then samples were incubated with an anti-LDHA antibody (Cell Signaling Technology, 1:100). Blocking of endogenous peroxidase and protein detection were performed
Results
LDHA expression is upregulated in the neointima of a balloon-injured rat carotid artery and in PDGF- or FBS-stimulated VSMCs.
To elucidate the role of LDHA in the proliferation and migration of VSMCs, we first measured the expression levels of LDHA in the balloon injury-induced neointima and growth factor-stimulated VSMCs. Immunohistochemical staining showed that LDHA expression was significantly higher in the neointimal region of rat carotid arteries after balloon angioplasty than in the
Discussion
The present study showed that upregulation of LDHA and increased glycolysis in growth factor-stimulated VSMCs play an important role in their proliferation and migration. Stimulation of VSMCs with PDGF led to an increased glycolytic rate accompanied by elevated cellular glucose uptake and lactate production. It also enhanced glucose oxidation and ATP production in VSMCs. However, inhibition of LDHA significantly suppressed PDGF-stimulated glycolysis and glucose oxidation, and also markedly
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgments
This work was supported by grants (NRF-2015R1A2A1A15053422, NRF-2015R1C1A2A01053565 and NRF-2015R1A2A1A10052745) from the National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning, and by grants (HI16C1501, HI15C0001 and HI13C1905) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. a grant of the Korea Health.
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2022, Journal of ProteomicsCitation Excerpt :In addition to its role in converting pyruvate to lactate, LDH also converts NADH into NAD+ [52,53]. The majority of studies on LDHA have focused on the cancer model and considered it as a target to control the proliferation and metastasis of cancer cells [54–56], some studies have also shown that LDHA is a key enzyme necessary for the proliferation and migration of VSMCs [57]. During the proliferation of vascular smooth muscle cells, glycolysis is increased in a Warburg-like manner, and this particular metabolic reprogramming is significant in determining phenotypes and signal transduction processes.
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These authors contributed equally.