Role of Kallistatin Treatment in Aging and Cancer by Modulating miR‐34a and miR‐21 Expression

Kallistatin is an endogenous protein that regulates differential signaling pathways and a wide spectrum of biological activities via its two structural elements: an active site and a heparin‐binding domain. Kallistatin via its heparin‐binding site inhibits vascular inflammation and oxidative stress by antagonizing TNF‐α‐induced NADPH oxidase activity, NF‐κB activation, and inflammatory gene expression in endothelial cells. Moreover, kallistatin via its active site inhibits microRNA‐34a (miR‐34a) synthesis and stimulates eNOS and SIRT1 expression in endothelial progenitor cells, whereas its heparin‐binding site is crucial for blocking TNF‐α‐induced miR‐21 expression and oxidative stress, thus reducing cellular senescence. By downregulating miR‐34a and miR‐21 expression, kallistatin treatment attenuates oxidative damage and aortic senescence in streptozotocin‐induced diabetic mice and extends Caenorhabditis elegans lifespan under stress conditions. Likewise, kallistatin through the heparin‐binding site inhibits TGF‐β‐induced miR‐21 synthesis and oxidative stress in endothelial cells, resulting in inhibition of endothelial‐mesenchymal transition, a process contributing to fibrosis and cancer. Furthermore, kallistatin’s active site is essential for stimulating miR‐34a and p53 expression and inhibiting the miR‐21‐Akt‐Bcl‐2 signaling pathway, thus inducing apoptosis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in protection against senescence, aging, and cancer development by modulating miR‐34a and miR‐21 levels and inhibiting oxidative stress.