Nε-carboxymethyl-lysine promotes calcium deposition in VSMCs via intracellular oxidative stress-induced PDK4 activation and alters glucose metabolism.

Wen-Qi Ma,Xin Wang,Yi Zhu,Ying Wang,Xi-Qiong Han,Nai-Feng Liu

doi:10.18632/oncotarget.22835

Wen-Qi Ma, Xin Wang + Show 4 more

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https://doi.org/10.18632/oncotarget.22835

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Journal: Oncotarget	Publication Date: Dec 1, 2017
Citations: 27	License type: cc-by

Affiliation: Zhongda Hospital Southeast University

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Diabetes and vascular calcification are intrinsically linked. We previously reported that advanced glycation end products (AGEs) accelerate calcium deposition in vascular smooth muscle cells (VSMCs) via excessive oxidative stress. However, the underlying mechanism remains poorly understood. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy metabolism. Since hyperactivation of PDK4 has been reported in calcified vessels and in patients with diabetes mellitus, inhibition of PDK4 expression may be a strategy for the prevention of diabetic vascular calcification. In this study, we used a rat VSMC model to investigate the role of PDK4 in diabetic vascular calcification and further explore the underlying mechanisms. We observed that Nε-carboxymethyl-lysine (CML), which is a major immunogen of AGEs, accelerated calcium deposition in VSMCs through PDK4 activation. An elevated level of reactive oxygen species (ROS) acted as a signal transduction intermediate to increase PDK4 expression. Either inhibition of PDK4 expression or RAGE (receptor for AGEs) blockade attenuated CML-induced VSMC calcification, as shown by decreased alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression. Glucose consumption and lactate production were increased during CML-induced VSMC calcification. Importantly, CML accelerates glycolysis in VSMCs via a PDK4-dependent pathway. In conclusion, this study demonstrates a novel mechanism by which CML promotes VSMC calcification via PDK4 activation and alters glucose metabolism in VSMCs.

Highlights

Vascular calcification, characterized by the deposition of calcium phosphate in cardiovascular tissue, is an active and cell-mediated process involving either the intima or media of blood vessels
Since apoptosis has been reported to be involved in the calcification process [22], we employed flow cytometry with annexin V and propidium iodide (PI) staining and the terminal deoxynucleotidyl transferasemediated dUTP nick end labelling (TUNEL) assay to detect apoptotic cells and determine whether the effects of CML on vascular smooth muscle cells (VSMCs) calcification are caused by the activation of specific signalling pathways or by cell apoptosis
The results demonstrated that CML induced oxidative stress, which elevates the Pyruvate dehydrogenase kinase 4 (PDK4) expression and results in VSMC calcification via various signalling intermediates

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Introduction

Vascular calcification, characterized by the deposition of calcium phosphate in cardiovascular tissue, is an active and cell-mediated process involving either the intima or media of blood vessels. It is associated with increased cardiovascular morbidity and mortality, especially in high-risk populations, such as patients with diabetes, atherosclerosis, or end-stage renal disease [1]. Long-term hyperglycaemia is an important risk factor for severe cardiovascular complications, including accelerated atherosclerosis and medial calcification [6]. Hyperglycaemia strongly promotes bone matrix protein expression and ALP activity [10,11,12]

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