Angiotensin II requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells.
Angiotensin II requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells.
复制标题
DOI：
10.1371/journal.pone.0033211
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Salazar G
中科院分区：
文献类型：
--
作者：
Patrushev N;Seidel-Rogol B;Salazar G
衰老是哺乳动物衰老的标志，与心血管疾病的发生和发展有关。血管紧张素II(Ang II)信号和锌稳态失调随着年龄的增长而增加，并与心血管疾病有关，但这些过程之间的关系尚未被研究。我们采用血管紧张素转换酶II诱导的血管平滑肌细胞衰老模型，探讨锌在血管功能障碍中的作用。我们发现Ang II诱导的衰老是一个锌依赖的途径，它是由锌转运蛋白ZnT3和ZnT10的下调所介导的，这两个转运蛋白的作用是减少胞内锌。锌通过增加体内活性氧自由基(ROS)，激活NADPH氧化酶活性和Akt，下调ZnT_3和ZnT_(10)，诱导衰老，从而模拟AngⅡ。锌可增加Ang II诱导的衰老，而锌离子螯合剂TPEN以及过表达的ZnT3或ZnT10可降低ROS，防止衰老。利用HEK293细胞，我们发现ZnT10定位于循环内小体，并将锌转运到囊泡中，以防止锌中毒。锌和ZnT3/ZnT10的下调通过减少过氧化氢酶的表达而诱导衰老。同时，siRNA下调细胞内的过氧化氢酶可诱导细胞衰老，而siRNA下调细胞内的ZnT_3和ZnT_(10)会增加细胞内的ROS。锌、siZnT3和siZnT10通过下调ERK1/2的磷酸化，通过转录后机制下调过氧化氢酶。这些数据表明，锌的稳态功能障碍是通过降低锌的表达来促进衰老的，Ang II诱导的衰老是一个锌和ROS依赖的过程。我们的研究表明，锌还可能影响Ang II诱导的其他ROS依赖的过程，如血管紧张素转换酶II诱导的平滑肌细胞肥大和迁移。
Senescence, a hallmark of mammalian aging, is associated with the onset and progression of cardiovascular disease. Angiotensin II (Ang II) signaling and zinc homeostasis dysfunction are increased with age and are linked to cardiovascular disease, but the relationship among these processes has not been investigated. We used a model of cellular senescence induced by Ang II in vascular smooth muscle cells (VSMCs) to explore the role of zinc in vascular dysfunction. We found that Ang II-induced senescence is a zinc-dependent pathway mediated by the downregulation of the zinc transporters ZnT3 and ZnT10, which work to reduce cytosolic zinc. Zinc mimics Ang II by increasing reactive oxygen species (ROS), activating NADPH oxidase activity and Akt, and by downregulating ZnT3 and ZnT10 and inducing senescence. Zinc increases Ang II-induced senescence, while the zinc chelator TPEN, as well as overexpression of ZnT3 or ZnT10, decreases ROS and prevents senescence. Using HEK293 cells, we found that ZnT10 localizes in recycling endosomes and transports zinc into vesicles to prevent zinc toxicity. Zinc and ZnT3/ZnT10 downregulation induces senescence by decreasing the expression of catalase. Consistently, ZnT3 and ZnT10 downregulation by siRNA increases ROS while downregulation of catalase by siRNA induces senescence. Zinc, siZnT3 and siZnT10 downregulate catalase by a post-transcriptional mechanism mediated by decreased phosphorylation of ERK1/2. These data demonstrate that zinc homeostasis dysfunction by decreased expression of ZnT3 or ZnT10 promotes senescence and that Ang II-induced senescence is a zinc and ROS-dependent process. Our studies suggest that zinc might also affect other ROS-dependent processes induced by Ang II, such as hypertrophy and migration of smooth muscle cells.
登录
查看更多内容
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
3.2
作者：
Ferrario, CM
通讯作者：
Ferrario, CM
影响因子：
3.8
作者：
Chung, NJ;Walker, PA;Hogstrand, C
通讯作者：
Hogstrand, C
影响因子：
37.8
作者：
Kunieda, Takeshige;Minamino, Tohru;Komuro, Issei
通讯作者：
Komuro, Issei