| Abstrakt: |
Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells ( EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin ( STZ)-induced diabetic mice, and Caenorhabditis elegans ( C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and micro RNA-21 (miR-21) and p16 INK4a synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes. Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 ( SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a- SIRT1 pathway. [ABSTRACT FROM AUTHOR] |
