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Copper Ion from Cu2O Crystal Induces AMPK-Mediated Autophagy via Superoxide in Endothelial Cells

  • Seo, Youngsik (Department of Molecular Biology & Institute of Nanosensor and Biotechnology, Dankook University) ;
  • Cho, Young-Sik (Department of Chemistry, Dankook University) ;
  • Huh, Young-Duk (Department of Chemistry, Dankook University) ;
  • Park, Heonyong (Department of Molecular Biology & Institute of Nanosensor and Biotechnology, Dankook University)
  • Received : 2015.07.14
  • Accepted : 2015.09.19
  • Published : 2016.03.31

Abstract

Copper is an essential element required for a variety of functions exerted by cuproproteins. An alteration of the copper level is associated with multiple pathological conditions including chronic ischemia, atherosclerosis and cancers. Therefore, copper homeostasis, maintained by a combination of two copper ions ($Cu^+$ and $Cu^{2+}$), is critical for health. However, less is known about which of the two copper ions is more toxic or functional in endothelial cells. Cubic-shaped $Cu_2O$ and CuO crystals were prepared to test the role of the two different ions, $Cu^+$ and $Cu^{2+}$, respectively. The $Cu_2O$ crystal was found to have an effect on cell death in endothelial cells whereas CuO had no effect. The $Cu_2O$ crystals appeared to induce p62 degradation, LC3 processing and an elevation of LC3 puncta, important processes for autophagy, but had no effect on apoptosis and necrosis. $Cu_2O$ crystals promote endothelial cell death via autophagy, elevate the level of reactive oxygen species such as superoxide and nitric oxide, and subsequently activate AMP-activated protein kinase (AMPK) through superoxide rather than nitric oxide. Consistently, the AMPK inhibitor Compound C was found to inhibit $Cu_2O$-induced AMPK activation, p62 degradation, and LC3 processing. This study provides insight on the pathophysiologic function of $Cu^+$ ions in the vascular system, where $Cu^+$ induces autophagy while $Cu^{2+}$ has no detected effect.

Acknowledgement

Supported by : Dankook University

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