Hydrogen sulfide mediates cardioprotection through Nrf2 signaling.
Hydrogen sulfide mediates cardioprotection through Nrf2 signaling.
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DOI：
10.1161/circresaha.109.199919
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发表时间：
2009-08-14
影响因子：
20.1
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Calvert JW;Jha S;Gundewar S;Elrod JW;Ramachandran A;Pattillo CB;Kevil CG;Lefer DJ
最近出现的硫化氢（H2S）作为一种有效的心脏保护信号分子，有必要阐明其细胞保护机制。本研究采用体内药理学预处理（PC）模型评价H2S介导的心脏保护作用的潜在机制。H2S（100 μg/kg）或溶媒在心肌缺血前24小时通过静脉注射给予小鼠。然后使处理的和未处理的小鼠经受45分钟的心肌缺血，随后再灌注长达24小时，在此期间评估心肌梗死的程度，测量循环肌钙蛋白-I水平，并评估氧化应激的程度。在单独的研究中，在早期（30分钟和2小时）和晚期（24小时）PC期间从处理和未处理小鼠中收集心肌组织，以评价H2S的潜在细胞靶点。最初的研究表明，H2S对缺血性损伤提供了深刻的保护，如梗死面积、循环肌钙蛋白-I水平和氧化应激的显著降低所证明的。在PC早期，H2S增加了Nrf 2的核定位，Nrf 2是一种调节许多抗氧化剂基因表达的转录因子，并增加了PKCε和STAT-3的磷酸化。在PC晚期，H2S增加了抗氧化剂（HO-1和Trx 1）的表达，增加了HSP 90、HSP 70、Bcl-2、Bcl-xL和考克斯-2的表达，并且还使促凋亡原Bad失活。这些结果表明，H2S的心脏保护作用在很大程度上是由抗氧化剂和抗凋亡信号的组合介导的。
The recent emergence of hydrogen sulfide (H2S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. The current study evaluated potential mechanisms of H2S-mediated cardioprotection using an in vivo model of pharmacological preconditioning (PC). H2S (100 μg/kg), or vehicle was administered to mice via an intravenous injection 24 hr prior to myocardial ischemia. Treated and untreated mice were then subjected to 45 min of myocardial ischemia followed by reperfusion for up to 24 hr, during which time the extent of myocardial infarction was evaluated, circulating troponin-I levels were measured, and the degree of oxidative stress was evaluated. In separate studies myocardial tissue was collected from treated and untreated mice during the early (30 min and 2hr) and late (24 hr) PC periods to evaluate potential cellular targets of H2S. Initial studies revealed that H2S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin-I levels, and oxidative stress. During the early PC period H2S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants, and increased the phosphorylation of PKCε and STAT-3. During the late PC period, H2S increased the expression of antioxidants (HO-1 and Trx1), increased the expression of HSP90, HSP70, Bcl-2, Bcl-xL, and COX-2 and also inactivated the pro-apoptogen Bad. These results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and anti-apoptotic signaling.