Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK.
Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK.
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DOI：
10.1016/j.yjmcc.2018.01.011
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发表时间：
2018-03
影响因子：
5
通讯作者：
Calvert JW
中科院分区：
文献类型：
--
作者：
Shimizu Y;Polavarapu R;Eskla KL;Nicholson CK;Koczor CA;Wang R;Lewis W;Shiva S;Lefer DJ;Calvert JW
硫化氢(H_2S)是线粒体生物能量学的重要调节因子，但其在线粒体生物发生中的作用尚不清楚。利用遗传学和药理学方法，我们试图确定硫化氢水平是否直接影响心肌线粒体的含量。与野生型心脏相比，缺乏产生硫化氢的酶--胱硫醚γ-裂解酶(CSEKO)的小鼠心肌线粒体含量减少。相比之下，过量表达CSE(CSE TG)的小鼠和补充口服活性硫化氢释放前体药物SG-1002的小鼠，显示出心肌线粒体含量的增加。进一步的分析表明，心肌过氧化氢水平影响过氧化体增殖物激活受体γ辅活化子1α(Pgc1α)的核定位和转录活性，高水平有积极影响，低水平有负面影响。旨在评估潜在机制的研究发现，硫化氢需要AMP激活的蛋白激酶(AMPK)来诱导PGC1DNA信号转导和线粒体的生物发生。最后，我们发现在心力衰竭时应用SG-1002恢复H_2S水平增加了心肌线粒体的含量，改善了线粒体的呼吸，提高了ATP的产生效率，改善了心功能。综上所述，这些结果表明，硫化氢是心肌线粒体含量的重要调节因子，并证实了外源硫化氢可以通过AMPK-Pgc1α信号级联途径诱导线粒体的生物发生。
Hydrogen sulfide (H2S) is an important regulator of mitochondrial bioenergetics, but its role in regulating mitochondrial biogenesis is not well understood. Using both genetic and pharmacological approaches, we sought to determine if H2S levels directly influenced cardiac mitochondrial content. Mice deficient in the H2S-producing enzyme, cystathionine γ-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild-type hearts. In contrast, mice overexpressing CSE (CSE Tg) and mice supplemented with the orally active H2S-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac H2S levels influenced the nuclear localization and transcriptional activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) with higher levels having a positive influence and lower levels having a negative influence. Studies aimed at evaluating the underlying mechanisms found that H2S required AMP-activated protein kinase (AMPK) to induce PGC1α signaling and mitochondrial biogenesis. Finally, we found that restoring H2S levels with SG-1002 in the setting of heart failure increased cardiac mitochondrial content, improved mitochondrial respiration, improved ATP production efficiency, and improved cardiac function. Together, these results suggest that hydrogen sulfide is an important regulator of cardiac mitochondrial content and establishes that exogenous hydrogen sulfide can induce mitochondrial biogenesis via an AMPK-PGC1α signaling cascade.
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影响因子：
20.1
作者：
Calvert JW;Condit ME;Aragón JP;Nicholson CK;Moody BF;Hood RL;Sindler AL;Gundewar S;Seals DR;Barouch LA;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
20.1
作者：
Calvert JW;Jha S;Gundewar S;Elrod JW;Ramachandran A;Pattillo CB;Kevil CG;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
37.8
作者：
Calvert JW;Elston M;Nicholson CK;Gundewar S;Jha S;Elrod JW;Ramachandran A;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
5
作者：
Lubbers ER;Mohler PJ
通讯作者：
Mohler PJ
影响因子：
20.1
作者：
Mustafa AK;Sikka G;Gazi SK;Steppan J;Jung SM;Bhunia AK;Barodka VM;Gazi FK;Barrow RK;Wang R;Amzel LM;Berkowitz DE;Snyder SH
通讯作者：
Snyder SH