Endocrine Abstracts

Lipocalin 2 has become an important biomarker for kidney disease and it is important to now understand it’s role in cardiomyopathy and understand it’s direct effects on the heart. Autophagy is now established as a critical determinant of cardiac function and here we investigated regulation of cardiac autophagy by lipocalin-2 and the functional consequences. After treating H9c2 cells with lipocalin-2 we used transmission electron microscopy, Western blotting and immunofluorescence for LC3-II, tandem fluorescent LC3 overexpression and MagicRed assay for lysosomal cathepsin activity to show that lipocalin-2 reduced autophagic flux. Lipocalin-2 also reduced oxidative stress in response to hypoxia. This correlated with reduced insulin sensitivity which was reversed when rapamycin was used to stimulate autophagy. We also observed that lipocalin-2 induced cardiomyocyte apoptosis. Mechanistically, we have shown that lipocalin-2 increased intracellular iron levels to mediate pro-apoptotic effects. We translated these studies to animal models by performing coronary artery ligation surgery to induce ischemia in wildtype and lipocalin-2 knockout mice. Our preliminary data indictaes that ischemia-induced caspase-3 and -12 activity was exaggerated in lipocalin-2 knockout versus wildtype. In summary, lipocalin-2 regulates cardiomyocyte autophagy, oxidative stress, apoptosis and insulin sensitivity and the exact physiological significance of these cardiac remodeling effects must now be determined.

Disclosure: Supported by a grant from Heart & Stroke Foundation of Canada