Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation

Guoxiong Xu, Jin Hee Ahn, So Young Chang, Megumi Eguchi, Arnaud Ogier, Sung Jun Han, Young Sam Park, Chi Young Shim, Yang Soo Jang, Bo Yang, Aimin Xu, Yu Wang, Gary Sweeney

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Abstract

Our objective was to determine whether lipocalin-2 (Lcn2) regulates cardiomyocyte apoptosis, the mechanisms involved, and the functional significance. Emerging evidence suggests that Lcn2 is a proinflammatory adipokine associated with insulin resistance and obesity-related complications, such as heart failure. Here, we used both primary neonatal rat cardiomyocytes and H9c2 cells and demonstrated for the first time that Lcn2 directly induced cardiomyocyte apoptosis, an important component of cardiac remodeling leading to heart failure. This was shown by detection of DNA fragmentation using TUNEL assay, phosphatidylserine exposure using flow cytometry to detect annexin V-positive cells, caspase-3 activity using enzymatic assay and immunofluorescence, and Western blotting for the detection of cleaved caspase-3. We also observed that Lcn2 caused translocation of the proapoptotic protein Bax to mitochondria and disruption of mitochondrial membrane potential. Using transient transfection of GFP-Bax, we confirmed that Lcn2 induced co-localization of Bax with MitoTracker® dye. Importantly, we used the fluorescent probe Phen Green SK to demonstrate an increase in intracellular iron in response to Lcn2, and depleting intracellular iron using an iron chelator prevented Lcn2-induced cardiomyocyte apoptosis. Administration of recombinant Lcn2 to mice for 14 days increased cardiomyocyte apoptosis as well as an acute inflammatory response with compensatory changes in cardiac functional parameters. In conclusion, Lcn2-induced cardiomyocyte apoptosis is of physiological significance and occurs via a mechanism involving elevated intracellular iron levels and Bax translocation.

Original languageEnglish
Pages (from-to)4808-4817
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number7
DOIs
Publication statusPublished - 2012 Feb 10

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Xu, G., Ahn, J. H., Chang, S. Y., Eguchi, M., Ogier, A., Han, S. J., Park, Y. S., Shim, C. Y., Jang, Y. S., Yang, B., Xu, A., Wang, Y., & Sweeney, G. (2012). Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation. Journal of Biological Chemistry, 287(7), 4808-4817. https://doi.org/10.1074/jbc.M111.275719