Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle - Role in cell survival
Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle - Role in cell survival
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DOI：
10.1074/jbc.m410413200
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发表时间：
2005-01-14
影响因子：
4.8
通讯作者：
Durante, W
中科院分区：
文献类型：
--
作者：
Liu, XM;Peyton, KJ;Durante, W
血红素加氧酶-1（HO-1）是一种细胞保护蛋白，催化血红素降解为胆绿素、铁和一氧化碳（CO）。在本研究中，我们发现，内质网（ER）应激诱导的各种实验剂刺激血管平滑肌细胞（SMC）HO-1 mRNA和蛋白的时间和浓度依赖性增加。雌激素受体应激对HO-1的诱导作用可被放线菌素D或放线菌酮阻断，并且与HO-1 mRNA稳定性的任何变化无关。荧光素酶报告分析表明，ER应激刺激HO-1启动子活性通过抗氧化反应元件。此外，ER应激诱导Nrf 2的核输入和Nrf 2与HO-1抗氧化反应元件的结合。有趣的是，内质网应激刺激SMC凋亡，表现为膜联蛋白V结合，半胱天冬酶-3激活，和DNA梯状。雌激素受体应激诱导的细胞凋亡被HO抑制增强，而它被阻止加入HO底物。此外，SMC暴露于外源性CO抑制ER应激介导的细胞凋亡，这与促凋亡蛋白GADD 153的表达减少有关。相反，其他HO- 1产物未能阻断ER应激过程中的细胞凋亡或GADD 153表达。这些结果表明，ER应激是血管SMC HO-1基因表达的诱导剂，HO-1衍生的CO以自分泌方式抑制SMC凋亡。ER应激刺激HO-1/CO系统的能力提供了一种新的机制，该细胞器通过该机制调节细胞存活。
Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide ( CO). In the present study, we found that endoplasmic reticulum ( ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO- 1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.