Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca(2+)/calmodulin-dependent protein kinase II.
Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca(2+)/calmodulin-dependent protein kinase II.
复制标题
通过 Ca(2)/钙调蛋白依赖性蛋白激酶 II 的 S-硫化作用改善心力衰竭中的线粒体功能障碍。
DOI：
10.1016/j.redox.2018.08.008
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Zhu YZ
中科院分区：
文献类型：
--
作者：
Wu D;Hu Q;Tan B;Rose P;Zhu D;Zhu YZ
Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）在心力衰竭的发展和诱导心肌线粒体损伤中起关键作用。最近的证据表明，由胱硫醚γ-裂解酶（CSE）产生的硫化氢（H2S）改善心力衰竭时的心功能。然而，其细胞机制在很大程度上仍然未知。本研究使用野生型和CSE敲除小鼠模型通过抑制CaMKII来确定H2S在保护心力衰竭中免于线粒体功能障碍中的功能作用。用S-丙基-L-半胱氨酸（SPRC）或硫氢化钠（NaHS）治疗，血液H2S水平的调节剂，减轻了动物心力衰竭的发展，减少了脂质过氧化，并保留了线粒体功能。如使用体内和体外模型所证明的，SPRC和NaHS对CaMKII磷酸化的抑制与这些化合物的心脏保护作用相对应。有趣的是，发现与野生型动物相比，CSE敲除（CSE-/-）小鼠中CaMKII活性升高，并且CaMKII的磷酸化状态似乎与心力衰竭的严重程度相关。重要的是，在野生型小鼠中，发现SPRC促进CaMKII的S-硫化，导致该蛋白质的活性降低，然而，在CSE-/-小鼠中，SPRC治疗后S-硫化被消除。一种新的机制描绘的作用，S-巯基化的CaMKII的调节。发现SPRC介导的CaMKII的S-巯基化抑制CAMKII活性并保持心血管稳态。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in the development of heart failure and in the induction of myocardial mitochondrial injury. Recent evidence has shown that hydrogen sulfide (H2S), produced by the enzyme cystathionine γ-lyase (CSE), improves the cardiac function in heart failure. However, the cellular mechanisms for this remain largely unknown. The present study was conducted to determine the functional role of H2S in protecting against mitochondrial dysfunction in heart failure through the inhibition of CaMKII using wild type and CSE knockout mouse models. Treatment with S-propyl-L-cysteine (SPRC) or sodium hydrosulfide (NaHS), modulators of blood H2S levels, attenuated the development of heart failure in animals, reduced lipid peroxidation, and preserved mitochondrial function. The inhibition CaMKII phosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds. Interestingly, CaMKII activity was found to be elevated in CSE knockout (CSE-/-) mice as compared to wild type animals and the phosphorylation status of CaMKII appeared to relate to the severity of heart failure. Importantly, in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein, however, in CSE-/- mice S-sulfhydration was abolished following SPRC treatment. A novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKII is presented. SPRC mediated S-sulfhydration of CaMKII was found to inhibit CAMKII activity and to preserve cardiovascular homeostasis.
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影响因子：
37.8
作者：
Rokita AG;Anderson ME
通讯作者：
Anderson ME
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
影响因子：
7.3
作者：
Altaany, Zaid;Ju, YoungJun;Wang, Rui
通讯作者：
Wang, Rui
影响因子：
7.4
作者：
Shen X;Pattillo CB;Pardue S;Bir SC;Wang R;Kevil CG
通讯作者：
Kevil CG
影响因子：
5
作者：
Grimm M;Brown JH
通讯作者：
Brown JH