Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner.
Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner.
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DOI：
10.1161/circheartfailure.115.002368
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Calvert JW
中科院分区：
文献类型：
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作者：
Shimizu Y;Nicholson CK;Lambert JP;Barr LA;Kuek N;Herszenhaut D;Tan L;Murohara T;Hansen JM;Husain A;Naqvi N;Calvert JW
旨在增加硫化氢（H2S）水平的治疗策略在各种心血管损伤模型中发挥细胞保护作用。然而，负责这种保护的基本机制仍有待充分阐明。核因子E2相关因子2（Nrf 2）是硫化氢的细胞靶点，是硫化氢介导的急性心肌梗死后心脏保护的促进剂。在这里，我们测试了Nrf 2介导H2S治疗在心力衰竭（HF）背景下的心脏保护作用的假设。对Nrf 2缺陷小鼠（12周龄）（Nrf 2 KO; C57 BL/6 J背景）和野生型（WT）同窝小鼠进行缺血诱导的HF。用硫化钠（Na 2S）形式的H2S处理的WT小鼠在诱导HF后显示出增强的Nrf 2信号传导，改善的左心室功能和较少的心脏肥大。相比之下，Na 2S治疗未能在Nrf 2 KO小鼠中提供针对HF的保护。旨在评估潜在心脏保护机制的研究发现，Na 2S增加了蛋白酶体亚单位的表达，导致蛋白酶体活性增加，受损蛋白质的积累减少。相比之下，Na 2S治疗未能增强蛋白酶体，也未能减弱Nrf 2 KO小鼠中受损蛋白的积累。此外，当蛋白酶体被抑制时，Na 2S不能改善心脏功能。这些发现表明，Na 2S治疗增强蛋白酶体的活性和功能，在心力衰竭的发展过程中，在Nrf 2依赖性的方式，这种增强导致心脏功能障碍的衰减。
Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear-factor-E2-related factor-2 (Nrf2) is a cellular target of H2S and facilitator of H2S-mediated cardioprotection following acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure (HF). Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type (WT) littermates were subjected to ischemic-induced HF. WT mice treated with H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left-ventricular function, and less cardiac hypertrophy following the induction of HF. In contrast, Na2S therapy failed to provide protection against HF in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S increased the expression of proteasome subunits, resulting in an increase proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na2S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na2S failed to improve cardiac function when the proteasome was inhibited. These findings indicate that Na2S therapy enhances proteasomal activity and function during the development of heart failure in an Nrf2-dependent manner and that this enhancement leads to attenuation in cardiac dysfunction.