Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation.


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.

DOI: 10.1074/jbc.M111.275719
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@article{Xu2012Lipocalin2IC, title={Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation.}, author={Guoxiong Xu and Jinhee Ahn and Soyoung Chang and Megumi Eguchi and Arnaud Ogier and Sungjun Han and Youngsam Park and Chiyoung Shim and Yangsoo Jang and Bo Yang and Aimin Xu and Yu Wang and G. J. Sweeney}, journal={The Journal of biological chemistry}, year={2012}, volume={287 7}, pages={4808-17} }