Open AccessKallistatin reduces vascular senescence and aging by regulating micro RNA ‐34a‐ SIRT 1 pathway
Author(s) -
Guo Youming,
Li Pengfei,
Gao Lin,
Zhang Jingmei,
Yang Zhirong,
Bledsoe Grant,
Chang Eugene,
Chao Lee,
Chao Julie
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12615
Subject(s) - oxidative stress , enos , senescence , biology , catalase , gene knockdown , microbiology and biotechnology , nitric oxide , chemistry , nitric oxide synthase , apoptosis , endocrinology , biochemistry
Summary 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 ( EPC s). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPC s, streptozotocin ( STZ )‐induced diabetic mice, and Caenorhabditis elegans ( C. elegans ). Human kallistatin significantly decreased TNF ‐α‐induced cellular senescence in EPC s, 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 INK 4a synthesis. Kallistatin prevented TNF ‐α‐mediated inhibition of SIRT 1, 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 SIRT 1 and eNOS synthesis in EPC s, 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 SIRT 1, 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 ( SIRT 1 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‐ SIRT 1 pathway.