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. Epub 2024 Apr 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadmium / toxicity
  • Cadmium Chloride
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Glucose Transporter Type 1* / genetics
  • Glucose Transporter Type 1* / metabolism
  • Glucose* / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Signal Transduction* / drug effects

Substances

  • Cadmium
  • Cadmium Chloride
  • Glucose
  • Glucose Transporter Type 1
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Slc2a1 protein, mouse