Testai L, Montanaro R, Flori L, Pagnotta E, Vellecco V, Gorica E, Ugolini L, Righetti L, Brancaleone V, Bucci M, Piragine E, Martelli A, Di Cesare Mannelli L, Ghelardini C, Calderone V
Department of Pharmacy, University of Pisa, 56120-Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy; Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, Pisa, Italy.
Department of Science, University of Basilicata, 85100, Potenza, Italy.
Biochem Pharmacol. 2023 Sep;215:115728. doi: 10.1016/j.bcp.2023.115728. Epub 2023 Jul 29.
Hydrogen sulfide (HS) is a gasotransmitter deeply involved in cardiovascular homeostasis and implicated in the myocardial protection against ischemia/reperfusion. The post-translational persulfidation of cysteine residues has been identified as the mechanism through which HS regulates a plethora of biological targets. Erucin (ERU) is an isothiocyanate produced upon hydrolysis of the glucosinolate glucoerucin, presents in edible plants of Brassicaceae family, such as Eruca sativa Mill., and it has emerged as a slow and long-lasting HS-donor.
In this study the cardioprotective profile of ERU has been investigated and the action mechanism explored, focusing on the possible role of the recently identified mitochondrial Kv7.4 (mitoKv7.4) potassium channels.
Interestingly, ERU showed to release HS and concentration-dependently protected H9c2 cells against HO-induced oxidative damage. Moreover, in in vivo model of myocardial infarct ERU showed protective effects, reducing the extension of ischemic area, the levels of troponin I and increasing the amount of total AnxA1, as well as co-related inflammatory outcomes. Conversely, the pre-treatment with XE991, a blocker of Kv7.4 channels, abolished them. In isolated cardiac mitochondria ERU exhibited the typical profile of a mitochondrial potassium channels opener, in particular, this isothiocyanate produced a mild depolarization of mitochondrial membrane potential, a reduction of calcium accumulation into the matrix and finally a flow of potassium ions. Finally, mitoKv7.4 channels were persulfidated in ERU-treated mitochondria.
ERU modulates the cardiac mitoKv7.4 channels and this mechanism may be relevant for cardioprotective effects.
硫化氢（HS）是一种气体信号分子，深度参与心血管稳态，并与心肌缺血/再灌注损伤的保护作用有关。半胱氨酸残基的翻译后过硫化已被确定为HS调节众多生物靶点的机制。萝卜硫素（ERU）是硫代葡萄糖苷葡萄糖萝卜硫素水解产生的异硫氰酸盐，存在于十字花科可食用植物中，如芝麻菜，它已成为一种缓慢且持久的HS供体。
本研究探讨了ERU的心脏保护作用及其作用机制，重点关注最近发现的线粒体Kv7.4钾通道的可能作用。
有趣的是，ERU显示出释放HS，并呈浓度依赖性地保护H9c2细胞免受HO诱导的氧化损伤。此外，在心肌梗死的体内模型中，ERU显示出保护作用，减少了缺血区域的范围、肌钙蛋白I的水平，并增加了总AnxA1的量以及相关的炎症反应。相反，用Kv7.4通道阻滞剂XE991预处理可消除这些作用。在分离的心脏线粒体中，ERU表现出线粒体钾通道开放剂的典型特征，特别是这种异硫氰酸盐使线粒体膜电位轻度去极化，减少了钙向基质的积累，最终导致钾离子流动。最后，在ERU处理的线粒体中，mitoKv7.4通道发生了过硫化。
ERU调节心脏mitoKv7.4通道，这一机制可能与心脏保护作用相关。
