Cathepsin Cleavage of Sirtuin 1 in Endothelial Progenitor Cells Mediates Stress-Induced Premature Senescence
Cathepsin Cleavage of Sirtuin 1 in Endothelial Progenitor Cells Mediates Stress-Induced Premature Senescence
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DOI：
10.1016/j.ajpath.2011.11.033
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发表时间：
2012-03-01
影响因子：
6
通讯作者：
Goligorsky, Michael S.
中科院分区：
文献类型：
--
作者：
Chen, Jun;Xavier, Sandhya;Goligorsky, Michael S.
应激诱导的内皮细胞（ECs）过早衰老（SIPS）已成为全球内皮细胞功能障碍的一个因素。与SIPS机制相关的细胞异常之一是溶酶体功能障碍。在这项研究中，我们研究了一系列心血管危险因素对SIRT1表达、SIPS和凋亡的影响，并记录了SIRT1在降低EC和内皮祖细胞（EPC）活力中的作用。这些发现在选择性敲除内皮细胞SIRT1的小鼠中得到证实。应激源的作用可以通过诱导溶酶体膜渗透或抑制自噬来部分模拟，并被组织蛋白酶抑制剂逆转。我们提供的证据表明，SIRT1是半胱氨酸组织蛋白酶B、S和l的重要底物。一种抗氧化剂/过氧亚硝酸盐清除剂ebselen，通过减轻溶酶体功能障碍，防止应激诱导的SIRT1耗尽和自噬的破坏。总之，我们的数据通过组织蛋白酶诱导的SIRT1蛋白水解裂解确立了溶酶体功能障碍在SIPS发展中的关键作用，从而提出了“干细胞衰老”的概念，这是一种将细胞应激与凋亡和SIPS联系起来的机制。Ebselen有效保护溶酶体膜完整性，阻止组织蛋白酶诱导的EPCs中SIRT - 1的裂解，减弱相关心血管应激源诱导的SIPS和凋亡细胞死亡。所提出的应激中SIRT1耗竭的机制具有EPCs SIPS范式的所有属性。（中华病理学杂志，2012,180:973-983;DOI: 10.1016/ j.j ajpath.2011.11.033）
Stress-induced premature senescence (SIPS) of endothelial cells (ECs) has emerged as a contributor to global EC dysfunction. One of the cellular abnormalities mechanistically linked to SIPS is lysosomal dysfunction. ha this study, we examined the impact of a range of cardiovascular risk factors on the expression of sirtuin 1 (SIRT1), SIPS, and apoptosis, and we documented the role of SIRT1 in reduced EC and endothelial progenitor cell (EPC) viability. These findings were confirmed in mice with selective endothelial SIRT1 knockout. The effects of stressors could be partially mimicked by inducing lysosomal membrane permeabilization or inhibiting autophagy, and were reversed by a cathepsin inhibitor. We provide evidence that SIRT1 is an important substrate of cysteine cathepsins B, S, and L. An antioxidant/peroxynitrite scavenger, ebselen, prevented stress-induced SIRT1 depletion and subversion of autophagy by mitigating lysosomal dysfunction. In conclusion, our data advance the concept of "stem cell aging" by establishing the critical role of lysosomal dysfunction in the development of SIPS through the cathepsin-induced proteolytic cleavage of SIRT1, a mechanism linking cell stress to apoptosis and SIPS. Ebselen potently protects lysosomal membrane integrity, preventing cathepsin-induced cleavage of SIRT 1 in EPCs and blunting SIPS and apoptotic cell death induced by relevant cardiovascular stressors. The proposed mechanism of SIRT1 depletion in stress has all of the attributes of being a paradigm of SIPS of EPCs. (Am J Pathol 2012, 180:973-983; DOI: 10.1016/j.ajpath.2011.11.033)