2. Academic Validation
  3. Cadmium contributes to cardiac metabolic disruption by activating endothelial HIF1A-GLUT1 axis

Cadmium contributes to cardiac metabolic disruption by activating endothelial HIF1A-GLUT1 axis

  • Cell Signal. 2024 Jul:119:111170. doi: 10.1016/j.cellsig.2024.111170.
Xiaoyu Zhang 1,  Wendan Zheng 1,  Shiyu Sun 1,  Yang Du 2,  Wenjuan Xu 3,  Zongguo Sun 4,  Fuhong Liu 4,  Manzhi Wang 5,  Zuohui Zhao 6,  Ju Liu 4,  Qiang Liu 7
Affiliations

Affiliations

  • 1 Department of Medical Physiology, School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong, China; Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
  • 2 Department of Personnel, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
  • 3 Department of Health Management, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering Laboratory for Health Management, Ji'nan, Shandong, China.
  • 4 Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
  • 5 Department of Hematology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
  • 6 Department of Pediatric Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
  • 7 Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China; Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Ji'nan, Shandong, China. Electronic address: qiangliu.sdu@gmail.com.
PMID: 38604344 DOI: 10.1016/j.cellsig.2024.111170
Abstract

Cadmium (Cd) is an environmental risk factor of cardiovascular diseases. Researchers have found that Cd exposure causes energy metabolic disorders in the heart decades ago. However, the underlying molecular mechanisms are still elusive. In this study, male C57BL/6 J mice were exposed to cadmium chloride (CdCl2) through drinking water for 4 weeks. We found that exposure to CdCl2 increased glucose uptake and utilization, and disrupted normal metabolisms in the heart. In vitro studies showed that CdCl2 specifically increased endothelial glucose uptake without affecting cardiomyocytic glucose uptake and endothelial fatty acid uptake. The glucose transporter 1 (GLUT1) as well as its transcription factor HIF1A was significantly increased after CdCl2 treatment in endothelial cells. Further investigations found that CdCl2 treatment upregulated HIF1A expression by inhibiting its degradation through ubiquitin-proteasome pathway, thereby promoted its transcriptional activation of SLC2A1. Administration of HIF1A small molecule inhibitor echinomycin and A-485 reversed CdCl2-mediated increase of glucose uptake in endothelial cells. In accordance with this, intravenous injection of echinomycin effectively ameliorated CdCl2-mediated metabolic disruptions in the heart. Our study uncovered the molecular mechanisms of Cd in contributing cardiac metabolic disruption by inhibiting HIF1A degradation and increasing GLUT1 transcriptional expression. Inhibition of HIF1A could be a potential strategy to ameliorate Cd-mediated cardiac metabolic disorders and Cd-related cardiovascular diseases.

Keywords

Cadmium; Cardiac metabolism; Endothelial cell; GLUT1; Glucose uptake; HIF1A.

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