Enduring Reactive Oxygen Species Emission Causes Aberrant Protein S-Glutathionylation Transitioning Human Aortic Valve Cells from a Sclerotic to a Stenotic Phenotype.
Enduring Reactive Oxygen Species Emission Causes Aberrant Protein S-Glutathionylation Transitioning Human Aortic Valve Cells from a Sclerotic to a Stenotic Phenotype.
复制标题
持久的活性氧排放导致异常的蛋白质 S-谷胱甘肽化，使人主动脉瓣细胞从硬化表型转变为狭窄表型。
DOI：
10.1089/ars.2021.0133
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发表时间：
2022
影响因子：
6.6
通讯作者：
Poggio,Paolo
中科院分区：
文献类型：
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作者：
Valerio,Vincenza;Keceli,Gizem;Moschetta,Donato;Porro,Benedetta;Ciccarelli,Michele;Massaiu,Ilaria;Songia,Paola;Maione,AngelaS;Alfieri,Valentina;Myasoedova,VeronikaA;Zanobini,Marco;Paolocci,Nazareno;Poggio,Paolo
目的：在钙化性主动脉瓣狭窄（CAVS）进展过程中，氧化应激和内皮功能障碍标志着抗氧化系统平行失调的初始致病步骤。在这里，我们测试了氧化诱导的蛋白s -谷胱甘肽化（P-SSG）是否解释了人类主动脉瓣组织的表型转换，最终导致钙沉积。接下来，我们测试了对抗这种活性氧（ROS）激增是否会阻止这些扰动。结果：我们采用了最先进的技术，如电子顺磁共振（EPR）、液相色谱-串联质谱、成像流式细胞术和活细胞成像，对人类切除的主动脉瓣和原代主动脉瓣内皮细胞（VECs）进行了检测。我们观察到，epr检测到的ROS排放净增加标志着人类CAVS标本从纤维化到钙化的转变，同时P-SSG沉积也在逐渐增加。在人类VECs （hVECs）中，2-乙酰氨基-3-[4-（2-乙酰氨基-2-羧乙基磺酰基硫代羰基氨基）苯基硫代氨基磺酰]丙酸引发高度氧化条件，促进P-SSG积累，破坏线粒体，并诱导内皮一氧化氮合酶解偶联。所有这些事件都使这些细胞从其原生内皮表型转变为受损的钙化诱导表型。作为原理证明，使用抗氧化剂n -乙酰- l-半胱氨酸可以防止这些变化。创新：作为一种面对过度氧化负担的代偿系统，随着时间的推移，P-SSG有助于hVECs从先天表型转变为受损表型，为钙沉积铺平道路。结论：我们的数据表明，在人主动脉瓣中，持续不断的ROS释放伴随着P-SSG的积累发生，并且至少部分地解释了导致cavs抗氧化的形态/功能变化。机械工程学报，36(2):481 - 481。
Aims:During calcific aortic valve stenosis (CAVS) progression, oxidative stress and endothelial dysfunction mark the initial pathogenic steps with a parallel dysregulation of the antioxidant systems. Here, we tested whether oxidation-induced protein S-glutathionylation (P-SSG) accounts for a phenotypic switch in human aortic valvular tissue, eventually leading to calcium deposition. Next, we tested whether countering this reactive oxygen species (ROS) surge would prevent these perturbations.Results:We employed state-of-the-art technologies, such as electron paramagnetic resonance (EPR), liquid chromatography-tandem mass spectrometry, imaging flow-cytometry, and live-cell imaging on human excised aortic valves and primary valve endothelial cells (VECs). We observed that a net rise in EPR-detected ROS emission marked the transition from fibrotic to calcific in human CAVS specimens, coupled to a progressive increment in P-SSG deposition. In human VECs (hVECs), treatment with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid triggered highly oxidizing conditions prompting P-SSG accumulation, damaging mitochondria, and inducing endothelial nitric oxide synthase uncoupling. All the events conjured up in morphing these cells from their native endothelial phenotype into a damaged calcification-inducing one. As proof of principle, the use of the antioxidant N-acetyl-L-cysteine prevented these alterations.Innovation:Borne as a compensatory system to face excessive oxidative burden, with time, P-SSG contributes to the morphing of hVECs from their innate phenotype into a damaged one, paving the way to calcium deposition.Conclusion:Our data suggest that, in the human aortic valve, unremitted ROS emission along with a P-SSG build-up occurs and accounts, at least in part, for the morphological/functional changes leading to CAVS.Antioxid. Redox Signal. 37, 1051–1071.