First Author | Guo Y | Year | 2018 |
Journal | J Cell Mol Med | Volume | 22 |
Issue | 9 | Pages | 4387-4398 |
PubMed ID | 29992759 | Mgi Jnum | J:265184 |
Mgi Id | MGI:6199544 | Doi | 10.1111/jcmm.13734 |
Citation | Guo Y, et al. (2018) Kallistatin attenuates endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway. J Cell Mol Med 22(9):4387-4398 |
abstractText | Kallistatin, a plasma protein, protects against vascular and organ injury. This study is aimed to investigate the role and mechanism of kallistatin in endothelial senescence. Kallistatin inhibited H2 O2 -induced senescence in human endothelial cells, as indicated by reduced senescence-associated-beta-galactosidase activity, p16(INK)(4a) and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked H2 O2 -induced superoxide formation, NADPH oxidase levels and VCAM-1, ICAM-1, IL-6 and miR-34a synthesis. Kallistatin reversed H2 O2 -mediated inhibition of endothelial nitric oxide synthase (eNOS), SIRT1, catalase and superoxide dismutase (SOD)-2 expression, and kallistatin alone stimulated the synthesis of these antioxidant enzymes. Moreover, kallistatin's anti-senescence and anti-oxidant effects were attributed to SIRT1-mediated eNOS pathway. Kallistatin, via interaction with tyrosine kinase, up-regulated Let-7g, whereas Let-7g inhibitor abolished kallistatin's effects on miR-34a and SIRT1/eNOS synthesis, leading to inhibition of senescence, oxidative stress and inflammation. Furthermore, lung endothelial cells isolated from endothelium-specific kallistatin knockout mice displayed marked reduction in mouse kallistatin levels. Kallistatin deficiency in mouse endothelial cells exacerbated senescence, oxidative stress and inflammation compared to wild-type mouse endothelial cells, and H2 O2 treatment further magnified these effects. Kallistatin deficiency caused marked reduction in Let-7g, SIRT1, eNOS, catalase and SOD-1 mRNA levels, and elevated miR-34a synthesis in mouse endothelial cells. These findings indicate that endogenous kallistatin through novel mechanisms protects against endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway. |