Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress

Kallistatin, via its two structural elements - an active site and a heparin-binding domain - displays a double-edged function in angiogenesis, apoptosis and oxidative stress. First, kallistatin has both anti-angiogenic and pro-angiogenic effects. Kallistatin treatment attenuates angiogenesis and tumor growth in cancer-bearing mice. Kallistatin via its heparin-binding site inhibits angiogenesis by blocking vascular endothelial growth factor (VEGF)-induced growth, migration and adhesion of endothelial cells. Conversely, kallistatin via the active site promotes neovascularization by stimulating VEGF levels in endothelial progenitor cells. Second, kallistatin inhibits or induces apoptosis depending on cell types. Kallistatin attenuates organ injury and apoptosis in animal models, and its heparin-binding site is essential for blocking tumor necrosis factor (TNF)-alpha-induced apoptosis in endothelial cells. However, kallistatin via its active site induces apoptosis in breast cancer cells by up-regulating miR-34a and down-regulating miR-21 and miR-203 synthesis. Third, kallistatin can act as an antioxidant or pro-oxidant. Kallistatin treatment inhibits oxidative stress and tissue damage in animal models and cultured cells. Kallistatin via the heparin-binding domain antagonizes TNF-alpha-induced oxidative stress, whereas its active site is crucial for stimulating antioxidant enzyme expression. In contrast, kallistatin provokes oxidant formation, leading to blood pressure reduction and bacterial killing. Kallistatin-mediated vasodilation is partly mediated by H2O2, as the effect is abolished by the antioxidant enzyme catalase. Moreover, kallistatin exerts a bactericidal effect by stimulating superoxide production in neutrophils of mice with microbial infection as well as in cultured immune cells. Thus, kallistatin's dual roles in angiogenesis, apoptosis and oxidative stress contribute to its beneficial effects in various diseases.