Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, USA.
Redox Biol. 2018 Oct;19:250-262. doi: 10.1016/j.redox.2018.08.008. Epub 2018 Aug 22.
Ca/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 (HS), 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 HS 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 HS 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.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）在心力衰竭的发展和心肌线粒体损伤的诱导中起着关键作用。最近的证据表明，由胱硫醚γ-裂解酶（CSE）产生的硫化氢（HS）可改善心力衰竭患者的心脏功能。然而，其细胞机制在很大程度上尚不清楚。本研究旨在通过使用野生型和 CSE 敲除小鼠模型，通过抑制 CaMKII 来确定 HS 在保护心力衰竭中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）处理，这两种血液 HS 水平的调节剂，可减轻动物心力衰竭的发展，减少脂质过氧化，并保护线粒体功能。SPRC 和 NaHS 在体内和体外模型中抑制 CaMKII 磷酸化的作用与这些化合物的心脏保护作用相对应。有趣的是，与野生型动物相比，CSE 敲除（CSE）小鼠中的 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有关。重要的是，在野生型小鼠中，发现 SPRC 促进 CaMKII 的 S-硫醇化，导致该蛋白活性降低，但在 CSE 小鼠中，SPRC 处理后 S-硫醇化被废除。
提出了一种新的机制，描述了 S-硫醇化在调节 CaMKII 中的作用。发现 SPRC 介导的 CaMKII 的 S-硫醇化可抑制 CAMKII 活性并维持心血管稳态。
