Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice.
Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice.
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DOI：
10.1161/circulationaha.109.920991
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发表时间：
2010-07-06
期刊：
影响因子：
37.8
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Calvert JW;Elston M;Nicholson CK;Gundewar S;Jha S;Elrod JW;Ramachandran A;Lefer DJ
硫化氢（H2S）是一种内源性信号分子，具有强大的细胞保护作用。本研究评价了硫化氢在心力衰竭小鼠模型中的治疗潜力。通过使小鼠永久性结扎左冠状动脉4周或使小鼠左冠状动脉闭塞60分钟然后再灌注4周来诱导心力衰竭。心脏限制性过表达H2S生成酶胱抑素γ-裂解酶（αMHC-CGL-Tg+）的转基因小鼠显示出明显的保护作用，可对抗缺血诱导心力衰竭引起的左心室结构和功能损害，并改善永久性心肌缺血引起的存活率。在再灌注时（心内）给予外源性H2S治疗（Na 2S; 100 μg/kg），然后在心肌缺血后的前7天每天（静脉内）给予外源性H2S治疗，也通过减轻氧化应激和线粒体功能障碍来防止左心室的结构和功能恶化。旨在阐明H2S治疗的一些保护机制的其他实验发现，7天的H2S治疗增加了Akt的磷酸化，并增加了2种转录因子（核呼吸因子1和核因子-E2相关因子（Nrf 2））的核定位，这些转录因子参与增加内源性抗氧化剂的水平，减弱细胞凋亡，并增加线粒体生物合成。本研究的结果表明，无论是外源性H2S的管理或内源性H2S生产的调制可能是在缺血性心力衰竭的治疗中的治疗益处。
Hydrogen sulfide (H2S) is an endogenous signaling molecule with potent cytoprotective effects. The present study evaluated the therapeutic potential of H2S in murine models of heart failure. Heart failure was induced by subjecting mice either to permanent ligation of the left coronary artery for 4 weeks or to 60 minutes of left coronary artery occlusion followed by reperfusion for 4 weeks. Transgenic mice with cardiac-restricted overexpression of the H2S-generating enzyme cystathione γ-lyase (αMHC-CGL-Tg+) displayed a clear protection against left ventricular structural and functional impairment as assessed by echocardiography in response to ischemia-induced heart failure, as well as improved survival in response to permanent myocardial ischemia. Exogenous H2S therapy (Na2S; 100 μg/kg) administered at the time of reperfusion (intracardiac) and then daily (intravenous) for the first 7 days after myocardial ischemia also protected against the structural and functional deterioration of the left ventricle by attenuating oxidative stress and mitochondrial dysfunction. Additional experiments aimed at elucidating some of the protective mechanisms of H2S therapy found that 7 days of H2S therapy increased the phosphorylation of Akt and increased the nuclear localization of 2 transcription factors, nuclear respiratory factor 1 and nuclear factor-E2-related factor (Nrf2), that are involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis. The results of the present study suggest that either the administration of exogenous H2S or the modulation of endogenous H2S production may be of therapeutic benefit in the treatment of ischemia-induced heart failure.