Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway.
Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway.
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DOI：
10.1111/acel.12615
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发表时间：
2017-08
期刊：
影响因子：
7.8
通讯作者：
Chao J
中科院分区：
文献类型：
--
作者：
Guo Y;Li P;Gao L;Zhang J;Yang Z;Bledsoe G;Chang E;Chao L;Chao J
Kallistatin是一种内源性蛋白质，通过抑制高血压大鼠的氧化应激和炎症，增强内皮祖细胞（EPCs）的运动性和功能，保护血管免受损伤。我们的目的是使用培养的EPCs、链脲佐菌素（STZ）诱导的糖尿病小鼠和秀丽隐杆线虫（C. elegans）来确定激肽释放酶抑制剂在血管衰老和老化中的作用和机制。人激肽他汀显著降低TNF-α诱导的EPCs细胞衰老，表现为衰老相关β-半乳糖苷酶活性和纤溶酶原激活物抑制剂-1表达降低以及端粒酶活性升高。Kallistatin阻断TNF-α诱导的超氧化物水平、NADPH氧化酶活性以及microRNA-21（miR-21）和p16 INK 4a合成。Kallistatin阻止了TNF-α介导的SIRT 1、eNOS和过氧化氢酶抑制，并直接刺激这些抗氧化酶的表达。此外，Kallistatin抑制miR-34 a的合成，而miR-34 a的过表达消除了Kallistatin诱导的抗氧化基因表达和抗衰老活性。Kallistatin通过其活性位点抑制miR-34 a，并刺激EPCs中SIRT 1和eNOS的合成，这被染料木黄酮消除，表明酪氨酸激酶介导的事件。此外，在糖尿病小鼠中，Kallistatin给药减弱了STZ诱导的主动脉衰老、氧化应激和miR-34 a和miR-21合成，并增加了SIRT 1、eNOS和过氧化氢酶水平。此外，在氧化或热应激下，激肽抑制素处理减少了超氧化物的形成并延长了野生型秀丽隐杆线虫的寿命，尽管激肽抑制素的保护作用在miR-34或sir-2.1（SIRT 1同源物）突变体秀丽隐杆线虫中被消除。在秀丽隐杆线虫中，Kallistatin抑制miR-34，但刺激sir-2.1和sod-3的合成。这些体内外研究为深入了解激肽通过调控miR-34 a-SIRT 1通路在血管衰老中的作用和机制提供了重要的线索。
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 microRNA‐21 (miR‐21) and p16INK 4a 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.
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DOI：
10.18632/aging.101068
发表时间：
2016-10-15
期刊：
Aging
影响因子：
--
作者：
Kitada M;Ogura Y;Koya D
通讯作者：
Koya D
影响因子：
5.5
作者：
Miao, RQ;Chen, V;Chao, J
通讯作者：
Chao, J
影响因子：
24
作者：
Heiss, C;Keymel, S;Kalka, C
通讯作者：
Kalka, C
DOI：
10.1016/s0022-2143(96)90152-3
发表时间：
1996-06-01
期刊：
JOURNAL OF LABORATORY AND CLINICAL MEDICINE
影响因子：
--
作者：
Chao, JL;Schmaier, A;Chao, L
通讯作者：
Chao, L
影响因子：
5
作者：
Gao, Lin;Yin, Hang;Chao, Julie
通讯作者：
Chao, Julie